Crystalline solids of mek inhibitor n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof

ABSTRACT

The present disclosure relates to: a) crystalline forms of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; b) pharmaceutical compositions comprising one or more crystalline forms of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and, optionally, one or more pharmaceutically acceptable carriers; c) methods of treating a tumor a cancer, or a Rasopathy disorder by administering one or more crystalline forms of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide to a subject in need thereof; and methods of producing essentially pure Form IV of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

FIELD OF THE INVENTION

The present disclosure relates to: a) methods of synthesizingN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;b) crystalline forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;c) pharmaceutical compositions comprising one or more crystalline formsofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,and, optionally, one or more pharmaceutically acceptable carriers; andd) methods of treating a tumor, a cancer, or a Rasopathy disorder byadministering one or more crystalline forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideto a subject in need thereof.

BACKGROUND

N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide(“mirdametinib”, or “PD-0325901”) is a small molecule drug which hasbeen designed to inhibit mitogen-activated protein kinase kinase 1(“MEK1”) and mitogen-activated protein kinase kinase 2 (“MEK2”). MEK1and MEK2 are proteins that play key roles in the mitogen-activatedprotein kinase (“MAPK”) signaling pathway. The MAPK pathway is criticalfor cell survival and proliferation, and overactivation of this pathway,has been shown to lead to tumor development and growth. Mirdametinib isa highly potent and specific allosteric non-ATP-competitive inhibitor ofMEK1 and MEK2. By virtue of its mechanism of action, mirdametinib leadsto significantly inhibited phosphorylation of the extracellularregulated MAP kinases ERK1 and ERK2, thereby leading to impaired growthof tumor cells both in vitro and in vivo. In addition, evidenceindicates that inflammatory cytokine-induced increases in MEK/ERKactivity contribute to the inflammation, pain, and tissue destructionassociated with rheumatoid arthritis and other inflammatory diseases.

Crystal forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidehave been described previously. WO2002/006213 describes crystallineForms I and II. U.S. Pat. No. 7,060,856 (“the '856 patent”) describes amethod of producing Form IV. The '856 patent indicates that the materialproduced by this method was greater than 90% Form IV (The '856 patent,Example 1). The '856 patent also states that the differential scanningcalorimetry (“DSC”) of the material produced shows an onset of meltingat 110° C. as well as a small peak with an onset at 117° C., consistentwith the material being a mixture of two forms.

WO 2006/134469 (“the '469 PCT publication”) also describes a method ofsynthesizingN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.The '469 PCT publication reports the method yields a product conformingto the polymorphic Form IV disclosed in U.S. patent application Ser. No.10/969,681 which issued as the '856 patent.

Differences in the characteristics of different polymorphic forms canlead to differences in the effective dose or physical propertiesaffecting processability ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecaused by differences in solubility or bioavailability. Thus, there is aneed for compositions of polymorphic forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,for use in treatment of a tumor, a cancer, or a Rasopathy disorder.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A is a X-ray powder diffraction pattern (“XRPD”) corresponding toessentially pure crystalline Form IV ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

FIG. 1B is a thermogravimetric analysis thermogram (“TGA”) and adifferential scanning calorimetry thermogram (“DSC”) corresponding toessentially pure crystalline Form IV ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

FIG. 2A is a X-ray powder diffraction pattern (“XRPD”) corresponding tocrystalline Form V.

FIG. 2B is a thermogravimetric analysis thermogram (“TGA”) and adifferential scanning calorimetry thermogram (“DSC”) corresponding tocrystalline Form V.

FIG. 3A is an XRPD corresponding to crystalline Form VI.

FIG. 3B is a DSC and a TGA corresponding to crystalline Form VI.

FIG. 4A is an XRPD corresponding to crystalline Form VII.

FIG. 4B is a DSC and a TGA corresponding to crystalline Form VII.

FIG. 5A is an XRPD corresponding to crystalline Form VIII.

FIG. 5B is a DSC and a TGA corresponding to crystalline Form VIII.

FIG. 6A is an XRPD corresponding to crystalline Form IX.

FIG. 6B is a DSC and a TGA corresponding to crystalline Form IX.

FIG. 7A is an XRPD corresponding to crystalline Form X.

FIG. 7B is a DSC and a TGA corresponding to crystalline Form X.

FIG. 8A is an XRPD corresponding to crystalline Form XI.

FIG. 8B is a DSC and a TGA corresponding to crystalline Form XI.

FIG. 9A is an XRPD corresponding to crystalline Form XII.

FIG. 9B is a DSC and a TGA corresponding to crystalline Form XII.

FIG. 10A is an XRPD corresponding to crystalline Form XIII.

FIG. 10B is a DSC and a TGA corresponding to crystalline Form XIII.

FIG. 11A is an XRPD corresponding to crystalline Form XIV overlaid withan XRPD corresponding to crystalline Form IV.

FIG. 11B is a DSC and a TGA corresponding to crystalline Form XIV.

FIG. 12A is an XRPD corresponding to crystalline Form XV.

FIG. 12B is a DSC and a TGA corresponding to crystalline Form XV.

FIG. 13A is an XRPD corresponding to crystalline Form XVI.

FIG. 13B is a DSC and a TGA corresponding to crystalline Form XVI.

FIG. 14A is an XRPD corresponding to crystalline Form XVII.

FIG. 14B is a DSC and a TGA corresponding to crystalline Form XVII.

FIG. 15A is an XRPD corresponding to crystalline Form XVIII.

FIG. 15B is a DSC and a TGA corresponding to crystalline Form XVIII.

FIG. 16A is an XRPD corresponding to crystalline Form XIX.

FIG. 16B is a DSC and a TGA corresponding to crystalline Form XIX.

FIG. 17A is an XRPD corresponding to crystalline Form XX.

FIG. 17B is a DSC and a TGA corresponding to crystalline Form XX.

FIG. 18A is an XRPD corresponding to crystalline Form XXI.

FIG. 18B is a DSC and a TGA corresponding to crystalline Form XXI.

FIG. 19A is an XRPD corresponding to crystalline Form XXII.

FIG. 19B is a DSC and a TGA corresponding to crystalline Form XXII.

FIG. 20A is an XRPD corresponding to crystalline Form XXIII.

FIG. 20B is a DSC and a TGA corresponding to crystalline Form XXIII.

FIG. 21A is an XRPD corresponding to crystalline Form XXIV.

FIG. 21B is a DSC and a TGA corresponding to crystalline Form XXIV.

FIG. 22A is an XRPD corresponding to amorphous mirdametinib.

FIG. 22B is a DSC and a TGA corresponding to amorphous mirdametinib.

BRIEF SUMMARY OF THE INVENTION

Crystalline Forms and Amorphous Solids

The present disclosure features useful compositions and methods to treatdisorders whereby aberrant MEK1 or MEK2 activity is implicated, e.g., acancer, a tumor, or a Rasopathy disorder, such as neurofibromatosis type1, in a subject in need thereof. In some aspects, the present disclosurefeatures novel polymorphic forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideand methods of producing them using pure Form IV, which is substantiallyfree of contaminating forms, e.g., Form I.

In some aspects, the present disclosure features novel methods ofsynthesizingN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.In some aspects, the methods of synthesizingN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein are useful in producing pure Form IV ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

In some aspects, the methods and compositions described herein areuseful in treating patients who struggle to swallow whole capsules ortablets, e.g., pediatric patients or subjects suffering from dysphagia,such as patients with esophageal cancer, Parkinson's disease,amyotrophic lateral sclerosis, stroke, achalasia, or esophagealnarrowing.

In some aspects, the present disclosure provides a crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideof Formula (I)

selected from the group consisting of:

-   a) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 5.4±0.2, 17.5±0.2,    and 22.8±0.2 degrees two theta;-   b) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 5.9±0.2, 7.2±0.2,    and 21.2±0.2 degrees two theta;-   c) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 5.3±0.2, 10.6±0.2,    and 16.1±0.2 degrees two theta;-   d) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 5.4±0.2, 10.7±0.2,    and 18.7±0.2 degrees two theta;-   e) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 6.7±0.2, 13.5±0.2,    and 22.2±0.2 degrees two theta;-   f) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 10.6±0.2, 19.6±0.2,    and 24.8±0.2 degrees two theta;-   g) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 5.5±0.2, 6.9±0.2,    and 10.1±0.2 degrees two theta;-   h) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 10.1±0.2, 17.3±0.2,    and 22.6±0.2 degrees two theta;-   i) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 4.6±0.2, 5.1±0.2,    and 14.6±0.2 degrees two theta;-   j) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 4.6±0.2, 23.4±0.2,    and 25.2±0.2 degrees two theta;-   k) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 5.5±0.2, 14.7±0.2,    and 20.9±0.2 degrees two theta;-   l) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 6.0±0.2, 17.1±0.2,    and 20.6±0.2 degrees two theta;-   m) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 5.9±0.2, 10.1±0.2,    and 15.5±0.2 degrees two theta;-   n) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 4.6±0.2, 10.7±0.2,    and 15.9±0.2 degrees two theta;-   o) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 10.2±0.2, 11.6±0.2,    and 20.0±0.2 degrees two theta;-   p) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 7.8±0.2, 14.0±0.2,    and 17.1±0.2 degrees two theta;-   q) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 5.5±0.2, 8.2±0.2,    and 16.7±0.2 degrees two theta;-   r) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 7.2±0.2, 21.7±0.2,    and 29.1±0.2 degrees two theta;-   s) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 5.4±0.2, 9.7±0.2,    and 10.7±0.2 degrees two theta; and-   t) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 7.2±0.2, 20.6±0.2,    and 23.0±0.2 degrees two theta.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks 5.4±0.2, 17.5±0.2, and22.8±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks 5.4±0.2, 12.5±0.2,17.5±0.2, and 22.8±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 2A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 2.7 wt % between about 35° C. and about 100° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 77° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 95° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 77°C. and a second endotherm onset at about 95° C. In some aspects, whereinthe crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG. 2B;and/or b) a DSC profile substantially as shown in FIG. 2B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form V.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.9±0.2, 7.2±0.2,and 21.2±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.9±0.2, 7.2±0.2,9.3±0.2, and 21.2±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 3A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 2.4 wt % between about 25° C. and about 125° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 41° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 70° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 109° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 41° C.and an endotherm onset at about 70° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 41° C.and an endotherm onset at about 109° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 70° C.and an endotherm onset at about 109° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 41°C., a second endotherm onset at about 70° C., and a third endothermonset at about 109° C. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG. 3B;and/or b) a DSC profile substantially as shown in FIG. 3B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form VI.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.3±0.2, 10.6±0.2,and 16.1±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.3±0.2, 10.6±0.2,13.9±0.2, and 16.1±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 4A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 5.2 wt % between about 40° C. and about 120° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 85° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endothermic event at about 110° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 85°C. and a second endothermic event at about 110° C. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG. 4B;and/or b) a DSC profile substantially as shown in FIG. 4B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form VII.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.4±0.2, 10.7±0.2,and 18.7±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.4±0.2, 10.7±0.2,18.7±0.2, and 23.9±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 5A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 3.3 wt % between about 40° C. and about 112° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 81° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 110° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 81°C. and a second endotherm onset at about 110° C. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG. 5B;and/or b) a DSC profile substantially as shown in FIG. 5B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form VIII.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 6.7±0.2, 13.5±0.2,and 22.2±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 6.7±0.2, 8.0±0.2,13.5±0.2, and 22.2±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 6A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 4.6 wt % between about 28° C. and about 128° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 84° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 107° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 114° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 84° C.and an endotherm onset at about 107° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 84° C.and an endotherm onset at about 114° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 107° C.and an endotherm onset at about 114° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 84°C., a second endotherm onset at about 107° C., and a third endothermonset at about 114° C. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG. 6B;and/or b) a DSC profile substantially as shown in FIG. 6B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form IX.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 10.6±0.2, 19.6±0.2,and 24.8±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.5±0.2, 10.6±0.2,19.6±0.2, and 24.8±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 7A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 2.9 wt % between about 40° C. and about 115° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 89° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG. 7B;and/or b) a DSC profile substantially as shown in FIG. 7B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form X.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.5±0.2, 6.9±0.2,and 10.1±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.5±0.2, 6.9±0.2,10.1±0.2, and 19.2±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 8A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 7.6 wt % between about 40° C. and about 175° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 69° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 104° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 69°C. and a second endotherm onset at about 104° C. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG. 8B;and/or b) a DSC profile substantially as shown in FIG. 8B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XI.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 10.1±0.2, 17.3±0.2,and 22.6±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 10.1±0.2, 17.3±0.2,21.5±0.2, and 22.6±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 9A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 8.5 wt % between about 40° C. and about 160° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 72° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 109° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 72°C. and a second endotherm onset at about 109° C. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG. 9B;and/or b) a DSC profile substantially as shown in FIG. 9B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XII.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 4.6±0.2, 5.1±0.2,and 14.6±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 4.6±0.2, 5.1±0.2,6.4±0.2, and 14.6±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 10A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 3.1 wt % between about 20° C. and about 100° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 55° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 109° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 55°C. and a second endotherm onset at about 109° C. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG.10B; and/or b) a DSC profile substantially as shown in FIG. 10B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XIII.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 4.6±0.2, 23.4±0.2,and 25.2±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 4.6±0.2, 23.4±0.2,25.2±0.2, and 30.6±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 11A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 0.15 wt % between about 40° C. and about 150° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 111° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG.11B; and/or b) a DSC profile substantially as shown in FIG. 11B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XIV.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.5±0.2, 14.7±0.2,and 20.9±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.5±0.2, 14.7±0.2,20.9±0.2, and 26.6±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 12A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 3.8 wt % between about 40° C. and about 150° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 104° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG.12B; and/or b) a DSC profile substantially as shown in FIG. 12B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XV.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 6.0±0.2, 17.1±0.2,and 20.6±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 6.0±0.2, 12.8±0.2,17.1±0.2, and 20.6±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 13A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 2.1 wt % between about 40° C. and about 150° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 74° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 102° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 114° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 74° C.and an endotherm onset at about 102° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 74° C.and an endotherm onset at about 114° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 102° C.and an endotherm onset at about 114° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 74°C., a second endotherm onset at about 102° C., and a third endothermonset at about 114° C. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG.13B; and/or b) a DSC profile substantially as shown in FIG. 13B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XVI.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.9±0.2, 10.1±0.2,and 15.5±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.9±0.2, 10.1±0.2,11.7±0.2, and 15.5±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 14A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 2.7 wt % between about 40° C. and about 100° C. In someaspects, crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 89° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG.14B; and/or b) a DSC profile substantially as shown in FIG. 14B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XVII.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 4.6±0.2, 10.7±0.2,and 15.9±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 4.6±0.2, 10.7±0.2,15.9±0.2, and 19.6±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 15A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 1.6 wt % between about 30° C. and about 150° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 83° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG.15B; and/or b) a DSC profile substantially as shown in FIG. 15B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XVIII.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 10.2±0.2, 11.6±0.2,and 20.0±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 10.2±0.2, 11.6±0.2,17.1±0.2, and 20.0±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 16A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 1.85 wt % between about 23° C. and about 92° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 69° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 98° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 115° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 69° C.and an endotherm onset at about 98° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 69° C.and an endotherm onset at about 115° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 98° C.and an endotherm onset at about 115° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 69°C., a second endotherm onset at about 98° C., and a third endothermonset at about 115° C. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG.16B; and/or b) a DSC profile substantially as shown in FIG. 16B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XIX.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 7.8±0.2, 14.0±0.2,and 17.1±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 7.8±0.2, 14.0±0.2,15.6±0.2, and 17.1±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 17A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 2.6 wt % between about 29° C. and about 126° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 77° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 92° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 110° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 77° C.and an endotherm onset at about 92° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 77° C.and an endotherm onset at about 110° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 92° C.and an endotherm onset at about 110° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 77°C., a second endotherm onset at about 92° C., and a third endothermonset at about 110° C. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG.17B; and/or b) a DSC profile substantially as shown in FIG. 17B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XX.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.5±0.2, 8.2±0.2,and 16.7±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.5±0.2, 8.2±0.2,16.7±0.2, and 17.7±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 18A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 14.1 wt % between about 30° C. and about 110° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram has an endotherm onset at about 52° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 90° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 52°C. and a second endotherm onset at about 90° C. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG.18B; and/or b) a DSC profile substantially as shown in FIG. 18B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XXI.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 7.2±0.2, 21.7±0.2,and 29.1±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 7.2±0.2, 18.6±0.2,21.7±0.2, and 29.1±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 19A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 13.8 wt % between about 26° C. and about 135° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 65° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 89° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 102° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 65° C.and an endotherm onset at about 89° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 65° C.and an endotherm onset at about 102° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 89° C.and an endotherm onset at about 102° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 65°C., a second endotherm onset at about 89° C., and a third endothermonset at about 102° C. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG.19B; and/or b) a DSC profile substantially as shown in FIG. 19B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XXII.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.4±0.2, 9.7±0.2,and 10.7±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.4±0.2, 6.5±0.2,9.7±0.2, and 10.7±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 20A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 4.4 wt % between about 27° C. and about 137° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 81° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 101° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 81°C. and a second endotherm onset at about 101° C. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG.20B; and/or b) a DSC profile substantially as shown in FIG. 20B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XXIII.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 7.2±0.2, 20.6±0.2,and 23.0±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 7.2±0.2, 9.5±0.2,20.6±0.2, and 23.0±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 21A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 1.2 wt % between about 30° C. and about 119° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 104° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG.21B; and/or b) a DSC profile substantially as shown in FIG. 21B.

In some aspects, the crystal form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XXIV.

In some aspects, the present disclosure provides an amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideof Formula (I)

In some aspects, the amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 22A.

In some aspects, the amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG.22B; and/or b) a DSC profile substantially as shown in FIG. 22B.

In some aspects, the XRPD pattern is generated using a PANALYTICAL®X'Pert Pro diffractometer using Ni-filtered Cu Kα (45 kV/40 mA)radiation and a step size of 0.03° 2θ with a X'CELERATOR® Real TimeMulti-Strip detector, configured (a) on the incidental beam side asfollows: variable divergence slits (10 mm irradiated length), 0.04 radSoller slits, fixed anti-scatter slit (0.50°), and 10 mm beam mask, and(b) on the diffracted beam side as follows: variable anti-scatter slit(10 mm observed length) and 0.04 rad Soller slit or a BRUKER® D8®ADVANCE™ system using Cu Kα (40 kV/40 mA) radiation and a step size of0.03° 2θ with a LYNXEYE™ detector, configured (a) on the incidental beamside as follows: Goebel mirror, mirror exit slit (0.2 mm), 2.5° Sollerslit, beam knife, and (b) on the diffracted beam side as follows:anti-scatter slit (8 mm) and 2.5° Soller slit; wherein samples aremounted flat on zero-background Si wafers. In some aspects, the DSCpattern is generated using a TA Instruments Q100 or Q2000 differentialscanning calorimeter at a rate of temperature increase of about 15°C./min.

Pharmaceutical Composition

In some aspects, the present disclosure is directed to a pharmaceuticalcomposition (e.g., capsule, tablet, powder, granules, minitablets, orpellets) comprising a crystalline form or amorphous solid ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein and one or more pharmaceutically acceptable carriers.

In some aspects, the pharmaceutical composition is for oraladministration. In some aspects, the pharmaceutical composition is asolid dosage form. In some aspects, the pharmaceutical composition is acapsule, tablet (e.g., dispersible tablet or orodispersible tablet),powder (e.g., dispersible powder), granules (e.g., dispersiblegranules), minitablets (e.g., dispersible minitablets), or pellets(e.g., dispersible pellets). In some aspects, the pharmaceuticalcomposition is a tablet (e.g., dispersible tablet or orodispersibletablet) or a capsule.

In some aspects, the pharmaceutical composition is a capsule. In someaspects, the capsule comprises about 1 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the capsule is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt % of the crystalline form or the amorphous solid ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more lubricants; and (e) a gelatincapsule which encapsulates components (a)-(d). In some aspects, thecapsule comprises about 1 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the capsule is as follows: (a) about 0.25wt/wt % to about 1.5 wt/wt % of the crystalline form or the amorphoussolid ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d)about 0.5 wt/wt % to about 2 wt/wt % of one or more lubricants; and (e)a gelatin capsule which encapsulates components (a)-(d).

In some aspects, the capsule comprises about 2 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the capsule is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt % of the crystalline form or the amorphous solid ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more lubricants; and (e) a gelatincapsule which encapsulates components (a)-(d). In some aspects, thecapsule comprises about 2 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the capsule is as follows: (a) about 0.25wt/wt % to about 1.5 wt/wt % of the crystalline form or the amorphoussolid ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d)about 0.5 wt/wt % to about 2 wt/wt % of one or more lubricants; and (e)a gelatin capsule which encapsulates components (a)-(d).

In some aspects, the capsule comprises about 5 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the capsule is as follows: (a) about 2.5 wt/wt% to about 7.0 wt/wt % of the crystalline form or the amorphous solid ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; and(d) a gelatin capsule which encapsulates components (a)-(c). In someaspects, the capsule comprises about 5 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the capsule is as follows: (a) about 2.5 wt/wt% to about 7.0 wt/wt % of the crystalline form or the amorphous solid ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; and(d) a gelatin capsule which encapsulates components (a)-(c).

In some aspects, the pharmaceutical composition is a tablet. In someaspects, the tablet comprises about 1 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the tablet is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt % of the crystalline form or the amorphous solid ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; and(d) 0 wt/wt % to about 5 wt/wt % of one or more lubricants. In someaspects, the tablet comprises about 1 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the tablet is as follows: (a) about 0.25 wt/wt% to about 1.5 wt/wt % of the crystalline form or the amorphous solid ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; and(d) about 0.5 wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the tablet comprises about 2 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the tablet is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt % of the crystalline form or the amorphous solid ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; and(d) 0 wt/wt % to about 5 wt/wt % of one or more lubricants. In someaspects, the tablet comprises about 2 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the tablet is as follows: (a) about 0.25 wt/wt% to about 1.5 wt/wt % of the crystalline form or the amorphous solid ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; and(d) about 0.5 wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the tablet comprises about 5 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the tablet is as follows: (a) about 2.5 wt/wt% to about 7.0 wt/wt % of the crystalline form or the amorphous solid ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; and(c) about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants. Insome aspects, the tablet comprises about 5 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the tablet is as follows: (a) about 2.5 wt/wt% to about 7.0 wt/wt % of the crystalline form or the amorphous solid ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; and(c) about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants.

In some aspects, the pharmaceutical composition is for oraladministration. In some aspects, the pharmaceutical composition isdispersible orodispersible.

In some aspects, the pharmaceutical composition is a tablet, a powder,granules, minitablets, or pellets (also called beads).

In some aspects, the pharmaceutical composition is a powder. In someaspects, the pharmaceutical composition is a dispersible powder. In someaspects, a capsule or sachet comprises the dispersible powder.

In some aspects, the pharmaceutical composition is in the form ofgranules. In some aspects, the granules are dispersible granules. Insome aspects, a capsule or sachet comprises the dispersible granules.

In some aspects, the pharmaceutical composition is in the form ofminitablets. In some aspects, the minitablets are dispersibleminitablets. In some aspects, a capsule or sachet comprises thedispersible minitablets.

In some aspects, the pharmaceutical composition is in the form ofpellets. In some aspects, the pellets are dispersible pellets. In someaspects, a capsule or sachet comprises the dispersible pellets.

In some aspects, the pharmaceutical composition is a tablet. In someaspects, the tablet is a dispersible tablet. In some aspects, the tabletis an orodispersible tablet.

In some aspects, the pharmaceutical composition that is a dispersibletablet, dispersible powder, dispersible granules, dispersibleminitablets, or dispersible pellets comprises about 0.1 mg to about 20mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the pharmaceutical composition is as follows:(a) about 0.1 wt/wt % to about 7 wt/wt % ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the pharmaceutical composition that is a dispersibletablet, dispersible powder, dispersible granules, dispersibleminitablets, or dispersible pellets comprises about 0.1 mg to about 20mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the pharmaceutical composition is as follows:(a) about 0.2 wt/wt % to about 1.5 wt/wt % ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 75 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 3 wt/wt % to about 8 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the pharmaceutical composition that is a dispersibletablet, dispersible powder, dispersible granules, dispersibleminitablets, or dispersible pellets comprises about 0.1 mg to about 20mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the pharmaceutical composition is as follows:(a) about 0.5 wt/wt % to about 1.2 wt/wt % ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the pharmaceutical composition that is a dispersibletablet, dispersible powder, dispersible granules, dispersibleminitablets, or dispersible pellets comprises about 0.5 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.In some aspects, the pharmaceutical composition comprises about 1 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.In some aspects, the pharmaceutical composition that is a dispersibletablet, dispersible powder, dispersible granules, dispersibleminitablets, or dispersible pellets comprises about 2 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.In some aspects, the pharmaceutical composition that is a dispersibletablet, dispersible powder, dispersible granules, dispersibleminitablets, or dispersible pellets comprises about 3 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.In some aspects, the pharmaceutical composition that is a dispersibletablet, dispersible powder, dispersible granules, dispersibleminitablets, or dispersible pellets comprises about 4 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

In some aspects, at least one of the diluents is selected from the groupconsisting of microcrystalline cellulose, lactose, mannitol, sorbitol,xylitol, sucrose, pregelatinized starch, calcium sulfate, calciumcarbonate, starch, and dibasic calcium phosphate. In some aspects, atleast one of the diluents is microcrystalline cellulose.

In some aspects, at least one of the disintegrants is selected from thegroup consisting of croscarmellose sodium, sodium starch glycolate,crospovidone, microcrystalline cellulose, starch, pregelatinized starch,low substituted hydroxypropyl cellulose, and alginic acid. In someaspects, at least one of the disintegrants is croscarmellose sodium.

In some aspects, at least one of the flavoring agents is selected fromthe group consisting of natural or synthetic flavors including but notlimited to, grape flavoring, bubble gum flavoring, caramel flavoring,orange flavoring, lemon flavoring, strawberry flavoring, raspberryflavoring, mint flavoring, peppermint flavoring, grapefruit flavoring,pineapple flavoring, pear flavoring, peach flavoring, vanilla flavoring,banana flavoring, or cherry flavoring. In some aspects, at least one ofthe flavoring agents is grape flavoring.

In some aspects, at least one of the sweeteners is selected from thegroup consisting of sucralose, acesulfame, saccharin, sucrose, xylitol,mannitol, sorbitol, glucose, fructose, and aspartame. In some aspects,at least one of the sweeteners is sucralose.

In some aspects, at least one of the lubricants is selected from thegroup consisting of magnesium stearate, sodium stearyl fumarate,glycerol dibehenate, stearic acid, hydrogenated vegetable oil, calciumstearate, zinc stearate, beeswax, colloidal silicon dioxide, and talc.In some aspects, at least one of the lubricants is magnesium stearate.

Methods of Treatment

In some aspects, the present disclosure provides a method of treating atumor, a cancer, or a Rasopathy disorder comprising administering to asubject in need of such treatment a pharmaceutical composition (e.g.,capsule, tablet, powder, granules, minitablets, or pellets) describedherein.

In some aspects, the present disclosure provides use of a pharmaceuticalcomposition (e.g., capsule, tablet, powder, granules, minitablets, orpellets) described herein for the manufacture of a medicament fortreating a tumor, a cancer, or Rasopathy disorder.

In some aspects, the tumor is a neurofibroma. In some aspects, the tumoris a neurofibroma associated with Neurofibromatosis Type 1. In someaspects, the tumor is selected from the group consisting of cutaneousneurofibroma, plexiform neurofibroma, optic pathway glioma, low gradeglioma, high grade glioma, or malignant peripheral nerve sheath tumor.In some aspects, the tumor is plexiform neurofibroma.

In some aspects, the subject has been diagnosed with a Rasopathydisorder selected from the group consisting of neurofibromatosis type 1,neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costellosyndrome, Legius syndrome, Noonan syndrome, and Noonan syndrome withmultiple lentigines.

In some aspects, the cancer is selected from the group consisting ofskin cancer, malignant peripheral nerve sheath cancer, leukemia,lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovariancancer, renal cancer, colorectal cancer, thyroid cancer,cholangiocarcinoma, urothelial cancer, uterine neoplasm, gastric cancer,sarcoma, bladder cancer, head and neck cancer, endometrial cancer,esophageal cancer, adenoid cystic carcinoma, gallbladder cancer,prostate cancer, oral cancer, cervical cancer, pancreatic cancer,melanoma, hepatocellular cancer, biliary tract cancer, and serouscarcinoma of the peritoneum. In some aspects, the leukemia is selectedfrom the group consisting of acute lymphocytic leukemia, acutemyelogenous leukemia, chronic lymphocytic leukemia, and chronicmyelogenous leukemia. In some aspects, the lymphoma is selected from thegroup consisting of B-cell lymphoma, T-cell lymphoma, Burkitt'slymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinalB cell lymphoma, small lymphocytic lymphoma, and Waldenstrommacroglobulinemia. In some aspects, the lung cancer is selected from thegroup consisting of lung adenocarcinoma, squamous non-small cell lungcancer, non-squamous non-small cell lung cancer, and small cell lungcancer.

In some aspects, the subject bears a mutation or other aberration in oneor more genes for which the mutation or other aberration causes a gainor loss of function characteristic of certain cancers, wherein themutation or other aberration in one or more genes is a mutation or otheraberration in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1,MAP2K4, NF1, or NF2.

In some aspects, an individual dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered as more than one capsule, more than one tablet (e.g.,dispersible tablet), more than one dose of powder (e.g., dispersiblepowder), more than one dose of granules (e.g., dispersible granules),more than one dose of minitablets (e.g., dispersible minitablets), morethan one dose of pellets (e.g., dispersible pellets), or a combinationthereof.

In some aspects, the pharmaceutical composition is a dispersible tablet,dispersible powder, dispersible granules, dispersible minitablets, ordispersible pellets, wherein the pharmaceutical composition is dispersedin a potable liquid prior to administration to the subject. For example,a dose of 3 mg of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecan be administered as two dispersible tablets—one containing 2 mg andthe other containing 1 mg or as three dispersible tablets eachcontaining 1 mg. As another example, a dose of 1.5 mg of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecan be administered as two dispersible dosage forms—one dispersibletablet containing 1 mg and a separate unit of dispersible powdercontaining 0.5 mg or as three units of dispersible powder eachcontaining 0.5 mg.

In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 20 mg. Insome aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 10 mg. Insome aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 8 mg. In someaspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 6 mg. In someaspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 2 mg. In someaspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 1 mg.

In some aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis about 0.1 mg to about 20 mg. In some aspects, the total daily dose oftheN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis about 0.5 mg. In some aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis about 1 mg. In some aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis about 2 mg. In some aspects, the total daily dose ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis about 4 mg. In some aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis about 6 mg. In some aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis about 8 mg. In some aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered about 20 mg.

In some aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily.

In some aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 0.1 mg to about 10 mgeach. In some aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 0.5 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 1 mg each. In someaspects, the total daily dose ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 2 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 3 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 4 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 10 mg each.

In some aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily. In some aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 0.1 mg to about 20 mg. Insome aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 0.5 mg. In some aspects,the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 1 mg. In some aspects, thetotal daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 2 mg. In some aspects, thetotal daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 4 mg. In some aspects, thetotal daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 8 mg. In some aspects, thetotal daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 10 mg. In some aspects,the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 20 mg.

In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 20 mg. Insome aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 10 mg. Insome aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 8 mg. In someaspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 6 mg. In someaspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 4 mg. In someaspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 2 mg. In someaspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 1 mg.

In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) 21 days inwhich the total daily dose is administered; and (b) 7 days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered. In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) 21 consecutivedays in which the total daily dose is administered; followed by (b) 7consecutive days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered.

In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) three 7-dayperiods each comprising (i) 5 days in which the total daily dose isadministered and (ii) 2 days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;and (b) 7 days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered. In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) three 7-dayperiods each comprising (i) 5 consecutive days in which the total dailydose is administered and (ii) 2 consecutive days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;followed by (b) 7 consecutive days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered.

In some aspects, the 28-day dosing cycle is repeated up to a total of 24consecutive 28-day dosing cycles.

In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising 28 days in which thetotal daily dose is administered.

In some aspects, the subject experiences dysphagia. In some aspects, thesubject experiences dysphagia caused by one or more of: disease of thenervous system, muscle weakening, developmental disability, stroke,injury, anatomical defect, cancer, treatment for cancer, allergicreaction, dementia, memory loss, or cognitive decline.

In some aspects, the subject is a pediatric subject.

Methods of PreparingN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideand Essentially Pure Form IV

Novel methods of producingN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideof Formula (I)

that comprise reacting PD-0315209 (FIPFA) and PD-0337792 (IPGA) with acoupling reagent that is 1-propylphosphonic anhydride (“T3P”) to obtain901 Acetonide, as shown in Scheme I below are disclosed herein.

In some aspects, the T3P is in solution. In some aspects, T3P isprovided as a solution in ethyl acetate.

In some aspects, the method of producing essentially pure Form IVN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideof Formula (I) comprises (a) reacting PD-0315209 (FIPFA) and PD-0337792(IPGA) with a coupling reagent that is T3P to obtain 901 Acetonide; and(b) treating 901 Acetonide with acid to formN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,as shown in Scheme II below.

In some aspects, the synthesis for essentially pure crystalline Form IVofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideof Formula (I) comprises the reaction set forth according to Scheme III.

In some aspects, the synthesis for essentially pure Form IV ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideof Formula (I) is as shown below in Scheme IV.

In some aspects, the methods provided herein provide a crystallinecomposition that is essentially pure Form IV ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidethat contains ≤0.2% of dimeric impurity PF-00191189

In some aspects, the crystalline composition contains about 0.05% toabout 0.19% by weight of dimeric impurity PF-00191189. In some aspects,the crystalline composition contains no detectable amount of dimericimpurity PF-00191189.

Definitions

To facilitate understanding of the disclosure set forth herein, a numberof terms are defined below.

Generally, the nomenclature used herein and the laboratory procedures inorganic chemistry, medicinal chemistry, and pharmacology describedherein are those well-known and commonly employed in the art. Unlessdefined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this disclosure belongs.

In this specification and the appended claims, the singular forms “a,”“an” and “the” include plural referents unless the context clearlydictates otherwise. The terms “a” (or “an”), as well as the terms “oneor more,” and “at least one” can be used interchangeably herein. Incertain aspects, the term “a” or “an” means “single.” In other aspects,the term “a” or “an” includes “two or more” or “multiple.”

Furthermore, “and/or” where used herein is to be taken as specificdisclosure of each of the two specified features or components with orwithout the other. Thus, the term “and/or” as used in a phrase such as“A and/or B” herein is intended to include “A and B,” “A or B,” “A”(alone), and “B” (alone). Likewise, the term “and/or” as used in aphrase such as “A, B, and/or C” is intended to encompass each of thefollowing aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; Aand C; A and B; B and C; A (alone); B (alone); and C (alone).

The terms “mirdametinib” and “PD-0325901” refer to the single enantiomerN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat,or mouse. The terms “subject” and “patient” are used interchangeablyherein in reference, for example, to a mammalian subject, such as ahuman subject.

The term “pediatric” refers to a human subject under the age of 21 yearsat the time of treatment. The term “pediatric” can be further dividedinto various subpopulations including: neonates (from birth through thefirst 28 days of life); infants (29 days of age to less than two yearsof age); children (two years of age to less than 12 years of age); andadolescents (12 years of age through 21 years of age (up to, but notincluding, the twenty-second birthday)). See, e.g., Berhman R E,Kliegman R, Arvin A M, Nelson W E. Nelson Textbook of Pediatrics, 15thEd. Philadelphia: W.B. Saunders Company, 1996; Rudolph A M, et al.Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First L R. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins;1994. Younger pediatric patients in particular, such as neonates,infants and young children, can have difficulty swallowing wholecapsules or tablets.

The term “dispersible” as used herein refers to a composition (e.g., atablet, powder, granules, minitablets, or pellets (also known as“beads”) which disintegrates and/or dissolves when combined with wateror another potable liquid (e.g., a non-water beverage), or a subject'sown saliva when placed in the subject's mouth, with or without theaddition of agitation or temperature modification. In some aspects, thedispersible composition disintegrates or dissolves within 10 minutes, 9minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3minutes, 2 minutes, or 1 minute after being combined with water oranother potable liquid. Such disintegration or dissolution need not becomplete. For example, a dispersible tablet may dissolve almostentirely, but some undissolved particulate matter may remain.

The term “orodispersible” refers to a composition which is capable ofdissolving or disintegrating in a subject's mouth (i.e., dissolving ordisintegrating in a subject's saliva) if administered orally, without arequirement of first dissolving or disintegrating in a separatecontainer.

As used herein, the terms “treat,” “treated,” and “treating” mean boththerapeutic treatment and prophylactic or preventative measures whereinthe object is to prevent or slow down (lessen) an undesiredphysiological condition, disorder, or disease, or obtain beneficial ordesired clinical results. Thus, those in need of treatment include thosealready diagnosed with or suspected of having the disorder. Beneficialor desired clinical results include, but are not limited to, alleviationof symptoms; diminishment of the extent of a condition, disorder, ordisease; stabilized (i.e., not worsening) state of condition, disorder,or disease; delay in onset or slowing of condition, disorder, or diseaseprogression; amelioration of the condition, disorder, or disease stateor remission (whether partial or total), whether detectable orundetectable; an amelioration of at least one measurable physicalparameter, not necessarily discernible by the patient; or enhancement orimprovement of condition, disorder, or disease. Treatment includeseliciting a clinically significant response without excessive levels ofside effects. Treatment also includes prolonging survival as compared toexpected survival if not receiving treatment. The term “therapeuticallyeffective amount” is meant to include the amount of a compound that,when administered, is sufficient to prevent development of, or alleviateto some extent, one or more of the symptoms of a disorder, disease, orcondition being treated. The term “therapeutically effective amount”also refers to the amount of a compound that is sufficient to elicit thebiological or medical response of a cell, tissue, system, animal, orhuman, which is being sought by a researcher, veterinarian, medicaldoctor, or clinician.

In certain aspects, a subject is successfully “treated” for a tumor,according to the methods described herein if the patient shows one ormore of the following: a reduction in the size of the tumor; relief ofone or more symptoms associated with the specific tumor; a reduction inthe volume of the tumor; improvement in quality of life; increasedprogression-free survival (PFS), disease-free survival (DFS), overallsurvival (OS), metastasis-free survival (MFS), complete response (CR),minimal residual disease (MRD), partial response (PR), stable disease(SD), a decrease in progressive disease (PD), an increased time toprogression (TTP), or any combination thereof. In some aspects,nationally or internationally accepted standards of treatment outcomesin a given tumor can be used to determine whether an effective amount ofmirdametinib meets any of these particular endpoints (e.g., CR, PFS,PR).

In certain aspects, a subject is successfully “treated” for cancer,e.g., lung cancer or ovarian cancer, according to the methods disclosedherein if the patient shows one or more of the following: a reduction inthe number of or complete absence of cancer cells; relief of one or moresymptoms associated with the specific cancer; reduced morbidity andmortality; improvement in quality of life; increased progression-freesurvival (PFS), disease-free survival (DFS), overall survival (OS),metastasis-free survival (MFS), complete response (CR), minimal residualdisease (MRD), partial response (PR), stable disease (SD), a decrease inprogressive disease (PD), an increased time to progression (TTP), or anycombination thereof. In some aspects, nationally or internationallyaccepted standards of treatment outcomes in a given cancer can be usedto determine whether an effective amount of mirdametinib meets any ofthese particular endpoints (e.g., CR, PFS, PR).

The terms “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” or“physiologically acceptable excipient” refer to a pharmaceuticallyacceptable material, composition, or vehicle, such as a liquid or solidexcipient, solvent, or encapsulating material. In one aspect, eachcomponent is “pharmaceutically acceptable” in the sense of beingcompatible with the other ingredients of a pharmaceutical formulation,and suitable for use in contact with the tissue or organ of humans andanimals without excessive toxicity, irritation, allergic response,immunogenicity, or other problems or complications, commensurate with areasonable benefit/risk ratio. See Remington: The Science and Practiceof Pharmacy, 21^(st) Edition, Lippincott Williams & Wilkins:Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5^(th)Edition, Rowe et al., Eds., The Pharmaceutical Press and the AmericanPharmaceutical Association: 2005; and Handbook of PharmaceuticalAdditives, 3^(rd) Edition, Ash and Ash Eds., Gower Publishing Company:2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRCPress LLC: Boca Raton, FL, 2004 (incorporated herein by reference).Excipients can include, for example: antiadherents, antioxidants,binders, coatings, compression aids, disintegrants, dyes (colors),emollients, emulsifiers, fillers (diluents), film formers or coatings,flavors, fragrances, glidants (flow enhancers), lubricants,preservatives, printing inks, sorbents, suspensing or dispersing agents,sweeteners, and waters of hydration. Exemplary excipients include, butare not limited to: butylated hydroxytoluene (BHT), calcium carbonate,calcium phosphate (dibasic), calcium stearate, calcium sulfate,croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid,crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropylcellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate,maltitol, mannitol, methionine, methylcellulose, methyl paraben,microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone,povidone, pregelatinized starch, propyl paraben, retinyl palmitate,shellac, silicon dioxide, sodium carboxymethyl cellulose, sodiumcitrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid,sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, andxylitol.

The term “pharmaceutical composition,” as used herein, represents acomposition containing a compound described herein formulated with oneor more pharmaceutically acceptable excipients (carriers), and can bemanufactured or sold with the approval of a governmental regulatoryagency as part of a therapeutic regimen for the treatment of disease ina mammal. Pharmaceutical compositions can be formulated, for example,for oral administration in unit dosage form (e.g., a tablet (e.g.,dispersible tablet), powder (e.g., dispersible powder) capsule,granules, minitablets, pellets, caplet, gelcap, or syrup).

The terms “about” or “approximately” means within a range of anacceptable error for a particular value as determined by one of ordinaryskill in the art, which depends in part on how the value is measured ordetermined. In some aspects, the term “about” or “approximately” meanswithin 1, 2, 3, or 4 standard deviations. In some aspects, the term“about” or “approximately” means a quantity, level, value, number,frequency, percentage, dimension, size, amount, weight or length thatvaries by as much as 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1%to a reference quantity, level, value, number, frequency, percentage,dimension, size, amount, weight or length.

As used herein, the term “administration” refers to the administrationof a composition (e.g., a compound or a preparation that includes acompound as described herein) to a subject or system. Administration toan animal subject (e.g., to a human) can be by any appropriate route,such as one described herein.

The term “solvate” refers to a compound provided herein or a saltthereof, which further includes a stoichiometric or non-stoichiometricamount of solvent bound by non-covalent intermolecular forces. Where thesolvent is water, the solvate is a hydrate. Where the solvent includesethanol, the compound can be an ethanol solvate.

The term “crystalline,” as used herein, refers to a solid-state formwhich consists of orderly arrangement of structural units. Differentcrystalline forms of the same compound, or a salt, hydrate, or solvatethereof, arise from different packing of the molecules in thesolid-state, which results in different crystal symmetries and/or unitcell parameter. Different crystalline forms usually have different X-raydiffraction patterns, infrared spectra, melting points, density,hardness, crystal shape, optical and electrical properties, stability,and solubility. See, e.g., Remington's Pharmaceutical Sciences, 18^(th)ed., Mack Publishing, Easton PA, 173 (1990); The United StatesPharmacopeia, 23^(rd) ed., 1843-1844 (1995) (incorporated herein byreference).

Crystalline forms are commonly characterized by X-ray powder diffraction(XRPD). An XRPD pattern of reflections (peaks, typically expressed indegrees 2-theta) is commonly considered a fingerprint of a particularcrystalline form. The relative intensities of the XRPD peaks can widelyvary depending on, inter alia, the sample preparation technique, crystalsize distribution, filters, the sample mounting procedure, and theparticular instrument employed. In some instances, new peaks may beobserved or existing peaks may disappear, depending on the type ofinstrument or the settings. In some instances, any particular peak in anXRPD pattern may appear as a singlet, doublet, triplet, quartet, ormultiplet, depending on the type of instrument or the settings, thesensitivity of the instrument, measuring conditions, and/or purity ofthe crystalline form. In some instances, any particular peak in an XRPDmay appear in a symmetric shape or in an asymmetric shape, e.g., havinga shoulder. Moreover, instrument variation and other factors can affectthe 2-theta values. A skilled artisan understanding these variations iscapable of discriminating or ascertaining the defining features orcharacteristics of a particular crystal form using XRPD, as well asusing other known physicochemical techniques.

The term “anhydrate” as applied to a compound refers to a crystallineform wherein the compound contains no structural water within thecrystal lattice.

As used herein, the term “essentially pure” with respect to Form IVmeans that the composition comprising Form IV contains no detectableamount of another polymorphic form (e.g., Form I or Form II), asdetermined by observing no detectable differences in an XRPD and/or DSCpattern between a single Form IV crystal and the crystalline compositionofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.However, “essentially pure” Form IV ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecan include impurities, such as, but not limited to, synthetic reactantsor by-products generated during the chemical synthesis.

As used herein, the term “aberration” as applied to a gene refers to amutation, chromosomal loss or fusion, epigenetic chemical modification,or other event which alters the sequence, level of expression, orprocessed mRNA sequence associated with a gene relative to the sequence,level of expression, or processed mRNA sequence associated with thewild-type gene.

It is understood that wherever aspects are described herein with thelanguage “comprising,” otherwise analogous aspects described in terms of“consisting of” and/or “consisting essentially of” are also provided.

The details of one or more aspects are set forth in the descriptionbelow. Other features, objects, and advantages will be apparent from thedescription and from the claims.

DETAILED DESCRIPTION OF THE INVENTION

Novel crystalline forms and amorphous solids ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideare described herein. Pharmaceutical compositions (e.g., capsules,tablets, dispersible and non-dispersible dosage forms) and methods totreat a patient in need of therapeutic administration ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideare also described herein. Additionally, a novel method of producing apure composition of crystalline Form IV ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis described herein.

Crystalline Forms and Amorphous Solids

The present disclosure relates in part to novel crystalline forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.As with all pharmaceutical compounds and compositions, the chemical andphysical properties ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideare important in its commercial development. These properties include,but are not limited to: (1) packing properties such as molar volume,bulk density and hygroscopicity, (2) thermodynamic properties such asmelting temperature, vapor pressure and solubility, (3) kineticproperties such as dissolution rate and stability (including stabilityat ambient conditions, especially to moisture and under storageconditions), (4) surface properties such as surface area, wettability,interfacial tension and shape, (5) mechanical properties such ashardness, tensile strength, compactability, handling, flow and blend;and (6) filtration properties. These properties can affect, for example,the processing and storage of the compound and pharmaceuticalcompositions comprising the compound.

In some aspects, the present disclosure provides a crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideof Formula (I)

selected from the group consisting of:

-   a) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 5.4 0.2, 17.5±0.2,    and 22.8±0.2 degrees two theta;-   b) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 5.9±0.2, 7.2±0.2,    and 21.2±0.2 degrees two theta;-   c) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 5.3±0.2, 10.6±0.2,    and 16.1±0.2 degrees two theta;-   d) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 5.4±0.2, 10.7±0.2,    and 18.7±0.2 degrees two theta;-   e) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 6.7±0.2, 13.5±0.2,    and 22.2±0.2 degrees two theta;-   f) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 10.6±0.2, 19.6±0.2,    and 24.8±0.2 degrees two theta;-   g) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 5.5±0.2, 6.9±0.2,    and 10.1±0.2 degrees two theta;-   h) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 10.1±0.2, 17.3±0.2,    and 22.6±0.2 degrees two theta;-   i) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 4.6±0.2, 5.1±0.2,    and 14.6±0.2 degrees two theta;-   j) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 4.6±0.2, 23.4±0.2,    and 25.2±0.2 degrees two theta;-   k) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 5.5±0.2, 14.7±0.2,    and 20.9±0.2 degrees two theta;-   l) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 6.0±0.2, 17.1±0.2,    and 20.6±0.2 degrees two theta;-   m) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 5.9±0.2, 10.1±0.2,    and 15.5±0.2 degrees two theta;-   n) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 4.6±0.2, 10.7±0.2,    and 15.9±0.2 degrees two theta;-   o) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 10.2±0.2, 11.6±0.2,    and 20.0±0.2 degrees two theta;-   p) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 7.8±0.2, 14.0±0.2,    and 17.1±0.2 degrees two theta;-   q) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 5.5±0.2, 8.2±0.2,    and 16.7±0.2 degrees two theta;-   r) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 7.2±0.2, 21.7±0.2,    and 29.1±0.2 degrees two theta;-   s) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 5.4±0.2, 9.7±0.2,    and 10.7±0.2 degrees two theta; and-   t) a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 7.2±0.2, 20.6±0.2,    and 23.0±0.2 degrees two theta.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks 5.4±0.2, 17.5±0.2, and22.8±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks 5.4±0.2, 12.5±0.2,17.5±0.2, and 22.8±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 2A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 2.7 wt % between about 35° C. and about 100° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 77° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 95° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 77°C. and a second endotherm onset at about 95° C. In some aspects, whereinthe crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG. 2B;and/or b) a DSC profile substantially as shown in FIG. 2B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form V.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.9±0.2, 7.2±0.2,and 21.2±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.9±0.2, 7.2±0.2,9.3±0.2, and 21.2±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 3A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 2.4 wt % between about 25° C. and about 125° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 41° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 70° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 109° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 41° C.and an endotherm onset at about 70° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 41° C.and an endotherm onset at about 109° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 70° C.and an endotherm onset at about 109° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 41°C., a second endotherm onset at about 70° C., and a third endothermonset at about 109° C. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG. 3B;and/or b) a DSC profile substantially as shown in FIG. 3B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form VI.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.3±0.2, 10.6±0.2,and 16.1±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.3 0.2, 10.6±0.2,13.9±0.2, and 16.1±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 4A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 5.2 wt % between about 40° C. and about 120° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 85° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endothermic event at about 110° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 85°C. and a second endothermic event at about 110° C. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG. 4B;and/or b) a DSC profile substantially as shown in FIG. 4B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form VII.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.4±0.2, 10.7±0.2,and 18.7±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.4±0.2, 10.7±0.2,18.7±0.2, and 23.9±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 5A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 3.3 wt % between about 40° C. and about 112° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 81° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 110° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 81°C. and a second endotherm onset at about 110° C. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG. 5B;and/or b) a DSC profile substantially as shown in FIG. 5B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form VIII.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 6.7±0.2, 13.5±0.2,and 22.2±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 6.7±0.2, 8.0±0.2,13.5±0.2, and 22.2±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 6A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 4.6 wt % between about 28° C. and about 128° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 84° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 107° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 114° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 84° C.and an endotherm onset at about 107° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 84° C.and an endotherm onset at about 114° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 107° C.and an endotherm onset at about 114° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 84°C., a second endotherm onset at about 107° C., and a third endothermonset at about 114° C. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG. 6B;and/or b) a DSC profile substantially as shown in FIG. 6B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form IX.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 10.6±0.2, 19.6±0.2,and 24.8±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.5±0.2, 10.6±0.2,19.6±0.2, and 24.8±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 7A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 2.9 wt % between about 40° C. and about 115° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 89° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG. 7B;and/or b) a DSC profile substantially as shown in FIG. 7B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form X.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.5±0.2, 6.9±0.2,and 10.1±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.5±0.2, 6.9±0.2,10.1±0.2, and 19.2±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 8A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 7.6 wt % between about 40° C. and about 175° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 69° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 104° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 69°C. and a second endotherm onset at about 104° C. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG. 8B;and/or b) a DSC profile substantially as shown in FIG. 8B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XI.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 10.1±0.2, 17.3±0.2,and 22.6±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 10.1±0.2, 17.3±0.2,21.5±0.2, and 22.6±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 9A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 8.5 wt % between about 40° C. and about 160° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 72° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 109° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 72°C. and a second endotherm onset at about 109° C. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG. 9B;and/or b) a DSC profile substantially as shown in FIG. 9B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XII.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 4.6±0.2, 5.1±0.2,and 14.6±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 4.6±0.2, 5.1±0.2,6.4±0.2, and 14.6±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 10A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 3.1 wt % between about 20° C. and about 100° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 55° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 109° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 55°C. and a second endotherm onset at about 109° C. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG.10B; and/or b) a DSC profile substantially as shown in FIG. 10B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XIII.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 4.6±0.2, 23.4±0.2,and 25.2±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 4.6±0.2, 23.4±0.2,25.2±0.2, and 30.6±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 11A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 0.15 wt % between about 40° C. and about 150° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 111° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG.11B; and/or b) a DSC profile substantially as shown in FIG. 11B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XIV.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.5±0.2, 14.7±0.2,and 20.9±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.5±0.2, 14.7±0.2,20.9±0.2, and 26.6±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 12A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 3.8 wt % between about 40° C. and about 150° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 104° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG.12B; and/or b) a DSC profile substantially as shown in FIG. 12B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XV.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 6.0±0.2, 17.1±0.2,and 20.6±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 6.0±0.2, 12.8±0.2,17.1±0.2, and 20.6±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 13A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 2.1 wt % between about 40° C. and about 150° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 74° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 102° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 114° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 74° C.and an endotherm onset at about 102° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 74° C.and an endotherm onset at about 114° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 102° C.and an endotherm onset at about 114° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 74°C., a second endotherm onset at about 102° C., and a third endothermonset at about 114° C. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG.13B; and/or b) a DSC profile substantially as shown in FIG. 13B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XVI.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.9±0.2, 10.1±0.2,and 15.5±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.9±0.2, 10.1±0.2,11.7±0.2, and 15.5±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 14A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 2.7 wt % between about 40° C. and about 100° C. In someaspects, crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 89° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG.14B; and/or b) a DSC profile substantially as shown in FIG. 14B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XVII.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 4.6±0.2, 10.7±0.2,and 15.9±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 4.6±0.2, 10.7±0.2,15.9±0.2, and 19.6±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 15A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 1.6 wt % between about 30° C. and about 150° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 83° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG.15B; and/or b) a DSC profile substantially as shown in FIG. 15B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XVIII.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 10.2±0.2, 11.6±0.2,and 20.0±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 10.2±0.2, 11.6±0.2,17.1±0.2, and 20.0±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 16A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 1.85 wt % between about 23° C. and about 92° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 69° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 98° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 115° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 69° C.and an endotherm onset at about 98° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 69° C.and an endotherm onset at about 115° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 98° C.and an endotherm onset at about 115° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 69°C., a second endotherm onset at about 98° C., and a third endothermonset at about 115° C. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG.16B; and/or b) a DSC profile substantially as shown in FIG. 16B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XIX.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 7.8±0.2, 14.0±0.2,and 17.1±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 7.8±0.2, 14.0±0.2,15.6±0.2, and 17.1±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 17A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 2.6 wt % between about 29° C. and about 126° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 77° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 92° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 110° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 77° C.and an endotherm onset at about 92° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 77° C.and an endotherm onset at about 110° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 92° C.and an endotherm onset at about 110° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 77°C., a second endotherm onset at about 92° C., and a third endothermonset at about 110° C. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG.17B; and/or b) a DSC profile substantially as shown in FIG. 17B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XX.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.5±0.2, 8.2±0.2,and 16.7±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.5±0.2, 8.2±0.2,16.7±0.2, and 17.7±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 18A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 14.1 wt % between about 30° C. and about 110° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram has an endotherm onset at about 52° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 90° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 52°C. and a second endotherm onset at about 90° C. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG.18B; and/or b) a DSC profile substantially as shown in FIG. 18B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XXI.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 7.2±0.2, 21.7±0.2,and 29.1±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 7.2±0.2, 18.6±0.2,21.7±0.2, and 29.1±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 19A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 13.8 wt % between about 26° C. and about 135° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 65° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 89° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 102° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 65° C.and an endotherm onset at about 89° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 65° C.and an endotherm onset at about 102° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 89° C.and an endotherm onset at about 102° C. In some aspects, the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 65°C., a second endotherm onset at about 89° C., and a third endothermonset at about 102° C. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG.19B; and/or b) a DSC profile substantially as shown in FIG. 19B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XXII.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.4±0.2, 9.7±0.2,and 10.7±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.4±0.2, 6.5±0.2,9.7±0.2, and 10.7±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 20A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 4.4 wt % between about 27° C. and about 137° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 81° C. Insome aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 101° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 81°C. and a second endotherm onset at about 101° C. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG.20B; and/or b) a DSC profile substantially as shown in FIG. 20B.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XXIII.

In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 7.2±0.2, 20.6±0.2,and 23.0±0.2 degrees two theta. In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 7.2±0.2, 9.5±0.2,20.6±0.2, and 23.0±0.2 degrees two theta. In some aspects, thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 21A.

In some aspects, the TGA exhibits that the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 1.2 wt % between about 30° C. and about 119° C. In someaspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 104° C.In some aspects, the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG.21B; and/or b) a DSC profile substantially as shown in FIG. 21B.

In some aspects, the crystal form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XXIV.

In some aspects, the present disclosure provides an amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideof Formula (I)

In some aspects, the amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 22A.

In some aspects, the amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by: a) a TGA profile substantially as shown in FIG.22B; and/or b) a DSC profile substantially as shown in FIG. 22B.

In some aspects, the XRPD pattern is generated using a PANALYTICAL®X'Pert Pro diffractometer using Ni-filtered Cu Kα (45 kV/40 mA)radiation and a step size of 0.03° 2θ with a X'CELERATOR® Real TimeMulti-Strip detector, configured (a) on the incidental beam side asfollows: variable divergence slits (10 mm irradiated length), 0.04 radSoller slits, fixed anti-scatter slit (0.500), and 10 mm beam mask, and(b) on the diffracted beam side as follows: variable anti-scatter slit(10 mm observed length) and 0.04 rad Soller slit or a BRUKER® D8®ADVANCE™ a system using Cu Kα (40 kV/40 mA) radiation and a step size of0.03° 2θ with a LYNXEYE™ detector, configured (a) on the incidental beamside as follows: Goebel mirror, mirror exit slit (0.2 mm), 2.5° Sollerslit, beam knife, and (b) on the diffracted beam side as follows:anti-scatter slit (8 mm) and 2.50 Soller slit; wherein samples aremounted flat on zero-background Si wafers. In some aspects, the DSCpattern is generated using a TA Instruments Q100 or Q2000 differentialscanning calorimeter at a rate of temperature increase of about 15°C./min.

Pharmaceutical Compositions

In some aspects, the present disclosure provides a pharmaceuticalcomposition comprising a crystalline form or amorphous solid ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein and one or more pharmaceutically acceptable carriers.

In some aspects, the desired crystalline form or amorphous solidcomprises less than 10% by weight total of one or more other crystallineforms and/or amorphous solid. In some aspects, the desired crystallineform or amorphous solid comprises less than 9% by weight total of one ormore other crystalline forms and/or amorphous solid. In some aspects,the desired crystalline form or amorphous solid comprises less than 8%by weight total of one or more other crystalline forms and/or amorphoussolid. In some aspects, the desired crystalline form or amorphous solidcomprises less than 7% by weight total of one or more other crystallineforms and/or amorphous solid. In some aspects, the desired crystallineform or amorphous solid comprises less than 6% by weight total of one ormore other crystalline forms and/or amorphous solid. In some aspects,the desired crystalline form or amorphous solid comprises less than 5%by weight total of one or more other crystalline forms and/or amorphoussolid. In some aspects, the desired crystalline form or amorphous solidcomprises less than 4% by weight total of one or more other crystallineforms and/or amorphous solid. In some aspects, the desired crystallineform or amorphous solid comprises less than 3% by weight total of one ormore other crystalline forms and/or amorphous solid. In some aspects,the desired crystalline form or amorphous solid comprises less than 2%by weight total of one or more other crystalline forms and/or amorphoussolid. In some aspects, the desired crystalline form or amorphous solidcomprises less than 1% by weight total of one or more other crystallineforms and/or amorphous solid. In some aspects, the desired crystallineform or amorphous solid comprises less than 0.5% by weight total of oneor more other crystalline forms and/or amorphous solid. In some aspects,the desired crystalline form or amorphous solid comprises less than 0.4%by weight total of one or more other crystalline forms and/or amorphoussolid. In some aspects, the desired crystalline form or amorphous formis essentially pure of other crystalline forms and/or amorphous solid.

In some aspects, the pharmaceutical composition is for oraladministration. In some aspects, the pharmaceutical composition is asolid dosage form. In some aspects, the pharmaceutical composition is acapsule, tablet (e.g., dispersible tablet), powder (e.g., dispersiblepowder), granules (e.g., dispersible granules), minitablets (e.g.,dispersible minitablets), or pellets (e.g., dispersible pellets). Insome aspects, the pharmaceutical composition (e.g., a dispersibletablet, dispersible powder, dispersible granules, dispersibleminitablets, or dispersible pellets) further comprises one or morepharmaceutically acceptable carriers. In some aspects, thepharmaceutical composition is for oral administration. In some aspects,the pharmaceutical composition is orodispersible.

In some aspects, the potable liquid is water, milk or a juice (e.g.,orange juice or apple juice). In some aspects, the potable liquid iswater. In some aspects, the potable liquid is a juice.

In some aspects, the pharmaceutical composition is a tablet, a powder,granules, minitablets, or pellets.

In some aspects, the pharmaceutical composition is a powder. In someaspects, the powder is a dispersible powder. In some aspects, a capsuleor sachet comprises the dispersible powder.

In some aspects, the pharmaceutical composition is in the form ofgranules. In some aspects, the granules are dispersible granules. Insome aspects, a capsule or sachet comprises the dispersible granules.

In some aspects, the pharmaceutical composition is in the form ofminitablets. In some aspects, the minitablets are dispersibleminitablets. In some aspects, a capsule or sachet comprises thedispersible minitablets.

In some aspects, the pharmaceutical composition is in the form ofpellets. In some aspects, the pellets are dispersible pellets. In someaspects, a capsule or sachet comprises the dispersible pellets.

In some aspects, the pharmaceutical composition is a tablet. In someaspects, the tablet is a dispersible tablet. In some aspects, thedispersible tablet is an orodispersible tablet.

In some aspects, the pharmaceutical composition comprises about 0.1 mg,about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg,about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.5 mg,about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg,about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, orabout 10 mg of one or more crystalline or amorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.In some aspects, the pharmaceutical composition comprises about 0.5 mgof one or more crystalline or amorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.In some aspects, the pharmaceutical composition comprises about 1 mg ofone or more crystalline or amorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.In some aspects, the pharmaceutical composition comprises about 2 mg ofone or more crystalline or amorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.In some aspects, the pharmaceutical composition comprises about 3 mg ofone or more crystalline or amorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.In some aspects, the pharmaceutical composition comprises about 4 mg ofone or more crystalline or amorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.In some aspects, the pharmaceutical composition comprises about 5 mg ofthe crystalline composition ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

In some aspects, the pharmaceutical composition comprises about 0.1wt/wt % to about 7 wt/wt % of one or more crystalline or amorphous formsofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.In some aspects, the pharmaceutical composition comprises about 0.1wt/wt % to about 5 wt/wt % of one or more crystalline or amorphous formsofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.In some aspects, the pharmaceutical composition comprises about 0.1wt/wt %, about 0.2 wt/wt %, about 0.3 wt/wt %, about 0.4 wt/wt %, about0.5 wt/wt %, about 0.6 wt/wt %, about 0.7 wt/wt %, about 0.8 wt/wt %,about 0.9 wt/wt %, about 1 wt/wt %, about 1.1 wt/wt %, about 1.2 wt/wt%, about 1.3 wt/wt %, about 1.4 wt/wt %, about 1.5 wt/wt %, about 1.6wt/wt %, about 1.7 wt/wt %, about 1.8 wt/wt %, about 1.9 wt/wt %, about2 wt/wt %, about 2.1 wt/wt %, about 2.2 wt/wt %, about 2.3 wt/wt %,about 2.4 wt/wt %, about 2.5 wt/wt %, about 2.6 wt/wt %, about 2.7 wt/wt%, about 2.8 wt/wt %, about 2.9 wt/wt %, about 3 wt/wt %, about 3.1wt/wt %, about 3.2 wt/wt %, about 3.3 wt/wt %, about 3.4 wt/wt %, about3.5 wt/wt %, about 3.6 wt/wt %, about 3.7 wt/wt %, about 3.8 wt/wt %,about 3.9 wt/wt %, about 4 wt/wt %, about 4.1 wt/wt %, about 4.2 wt/wt%, about 4.3 wt/wt %, about 4.4 wt/wt %, about 4.5 wt/wt %, about 4.6wt/wt %, about 4.7 wt/wt %, about 4.8 wt/wt %, about 4.9 wt/wt %, about5 wt/wt %, about 5.1 wt/wt %, about 5.2 wt/wt %, about 5.3 wt/wt %,about 5.4 wt/wt %, about 5.5 wt/wt %, about 5.6 wt/wt %, about 5.7 wt/wt%, about 5.8 wt/wt %, about 5.9 wt/wt %, about 6 wt/wt %, about 6.1wt/wt %, about 6.2 wt/wt %, about 6.3 wt/wt %, about 6.4 wt/wt %, about6.5 wt/wt %, about 6.6 wt/wt %, about 6.7 wt/wt %, about 6.8 wt/wt %,about 6.9 wt/wt %, or about 7 wt/wt % of one or more crystalline oramorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.In some aspects, the pharmaceutical composition comprises about 0.5wt/wt % of one or more crystalline or amorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.In some aspects, the pharmaceutical composition comprises about 0.8wt/wt % of one or more crystalline or amorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

In some aspects, the pharmaceutical composition comprises one or morediluents. In some aspects, the pharmaceutical composition comprisesabout 50 wt/wt % to about 98 wt/wt % of one or more diluents. In someaspects, the pharmaceutical composition comprises about 70 wt/wt % toabout 98 wt/wt % of one or more diluent. In some aspects, thepharmaceutical composition comprises about 85 wt/wt % to about 95 wt/wt% of one or more diluents. In some aspects, the pharmaceuticalcomposition comprises about 50 wt/wt %, about 51 wt/wt %, about 52 wt/wt%, about 53 wt/wt %, about 54 wt/wt %, about 55 wt/wt %, about 56 wt/wt%, about 57 wt/wt %, about 58 wt/wt %, about 59 wt/wt %, about 60 wt/wt%, about 61 wt/wt %, about 62 wt/wt %, about 63 wt/wt %, about 64 wt/wt%, about 65 wt/wt %, about 66 wt/wt %, about 67 wt/wt %, about 68 wt/wt%, about 69 wt/wt %, about 70 wt/wt %, about 71 wt/wt %, about 72 wt/wt%, about 73 wt/wt %, about 74 wt/wt %, about 75 wt/wt %, about 76 wt/wt%, about 77 wt/wt %, about 78 wt/wt %, about 79 wt/wt %, about 80 wt/wt%, about 81 wt/wt %, about 82 wt/wt %, about 83 wt/wt %, about 84 wt/wt%, about 85 wt/wt %, about 86 wt/wt %, about 87 wt/wt %, about 88 wt/wt%, about 89 wt/wt %, about 90 wt/wt %, about 91 wt/wt %, about 92 wt/wt%, about 93 wt/wt %, about 94 wt/wt %, about 95 wt/wt %, about 96 wt/wt%, about 97 wt/wt %, or about 98 wt/wt % of one or more diluents. Insome aspects, the pharmaceutical composition comprises about 90 wt/wt %of one or more diluents. In some aspects, the pharmaceutical compositioncomprises about 93 wt/wt % of one or more diluents.

In some aspects, at least one of the diluents is selected from the groupconsisting of microcrystalline cellulose, lactose, mannitol, sorbitol,xylitol, sucrose, pregelatinized starch, calcium sulfate, calciumcarbonate, starch, and dibasic calcium phosphate. In some aspects, atleast one of the diluents is microcrystalline cellulose.

In some aspects, the pharmaceutical composition comprises about 50 wt/wt% to about 98 wt/wt % microcrystalline cellulose. In some aspects, thepharmaceutical composition comprises about 70 wt/wt % to about 95 wt/wt% microcrystalline cellulose. In some aspects, the pharmaceuticalcomposition comprises about 85 wt/wt % to about 95 wt/wt %microcrystalline cellulose. In some aspects, the pharmaceuticalcomposition comprises about 50 wt/wt %, about 51 wt/wt %, about 52 wt/wt%, about 53 wt/wt %, about 54 wt/wt %, about 55 wt/wt %, about 56 wt/wt%, about 57 wt/wt %, about 58 wt/wt %, about 59 wt/wt %, about 60 wt/wt%, about 61 wt/wt %, about 62 wt/wt %, about 63 wt/wt %, about 64 wt/wt%, about 65 wt/wt %, about 66 wt/wt %, about 67 wt/wt %, about 68 wt/wt%, about 69 wt/wt %, about 70 wt/wt %, about 71 wt/wt %, about 72 wt/wt%, about 73 wt/wt %, about 74 wt/wt %, about 75 wt/wt %, about 76 wt/wt%, about 77 wt/wt %, about 78 wt/wt %, about 79 wt/wt %, about 80 wt/wt%, about 81 wt/wt %, about 82 wt/wt %, about 83 wt/wt %, about 84 wt/wt%, about 85 wt/wt %, about 86 wt/wt %, about 87 wt/wt %, about 88 wt/wt%, about 89 wt/wt %, about 90 wt/wt %, about 91 wt/wt %, about 92 wt/wt%, about 93 wt/wt %, about 94 wt/wt %, about 95 wt/wt %, about 96 wt/wt%, about 97 wt/wt %, or about 98 wt/wt % microcrystalline cellulose. Insome aspects, the pharmaceutical composition comprises about 90 wt/wt %microcrystalline cellulose. In some aspects, the pharmaceuticalcomposition comprises about 93 wt/wt % microcrystalline cellulose.

In some aspects, the pharmaceutical composition comprises about 1 wt/wt% to about 10 wt/wt % of one or more disintegrants. In some aspects, thepharmaceutical composition comprises about 3.5 wt/wt % to about 6 wt/wt% of one or more disintegrants. In some aspects, the pharmaceuticalcomposition comprises about 1.0 wt/wt %, about 1.1 wt/wt %4, about 1.2wt/wt %, about 1.3 wt/wt %, about 1.4 wt/wt %, about 1.5 wt/wt %, about1.6 wt/wt %, about 1.7 wt/wt %, about 1.8 wt/wt %, about 1.9 wt/wt %,about 2.0 wt/wt %, about 2.1 wt/wt %, about 2.2 wt/wt %, about 2.3 wt/wt%, about 2.4 wt/wt %, about 2.5 wt/wt %, about 2.6 wt/wt %, about 2.7wt/wt %, about 2.8 wt/wt %, about 2.9 wt/wt %, about 3.0 wt/wt %, about3.1 wt/wt %, about 3.2 wt/wt %, about 3.3 wt/wt %, about 3.4 wt/wt %,about 3.5 wt/wt %, about 3.6 wt/wt %, about 3.7 wt/wt %, about 3.8 wt/wt%, about 3.9 wt/wt %, about 4.0 wt/wt %, about 4.1 wt/wt %, about 4.2wt/wt %, about 4.3 wt/wt %, about 4.4 wt/wt %, about 4.5 wt/wt %, about4.6 wt/wt %, about 4.7 wt/wt %, about 4.8 wt/wt %, about 4.9 wt/wt %,about 5.0 wt/wt %, about 5.1 wt/wt %, about 5.2 wt/wt %, about 5.3 wt/wt%, about 5.4 wt/wt %, about 5.5 wt/wt %, about 5.6 wt/wt %, about 5.7wt/wt %, about 5.8 wt/wt %, about 5.9 wt/wt %, about 6.0 wt/wt %, about6.1 wt/wt %, about 6.2 wt/wt %, about 6.3 wt/wt %, about 6.4 wt/wt %,about 6.5 wt/wt %, about 6.6 wt/wt %, about 6.7 wt/wt %, about 6.8 wt/wt%, about 6.9 wt/wt %, about 7.0 wt/wt %, about 7.1 wt/wt %, about 7.2wt/wt %, about 7.3 wt/wt %, about 7.4 wt/wt %, about 7.5 wt/wt %, about7.6 wt/wt %, about 7.7 wt/wt %, about 7.8 wt/wt %, about 7.9 wt/wt %,about 8.0 wt/wt %, about 8.1 wt/wt %, about 8.2 wt/wt %, about 8.3 wt/wt%, about 8.4 wt/wt %, about 8.5 wt/wt %, about 8.6 wt/wt %, about 8.7wt/wt %, about 8.8 wt/wt %, about 8.9 wt/wt %, about 9.0 wt/wt %, about9.1 wt/wt %, about 9.2 wt/wt %, about 9.3 wt/wt %, about 9.4 wt/wt %,about 9.5 wt/wt %, about 9.6 wt/wt %, about 9.7 wt/wt %, about 9.8 wt/wt%, about 9.9 wt/wt %, or about 10.0 wt/wt % of one or moredisintegrants. In some aspects, the pharmaceutical composition comprisesabout 5 wt/wt % of one or more disintegrants.

In some aspects, at least one of the disintegrants is selected from thegroup consisting of croscarmellose sodium, sodium starch glycolate,crospovidone, microcrystalline cellulose, starch, pregelatinized starch,low substituted hydroxypropyl cellulose, and alginic acid. In someaspects, at least one of the disintegrants is croscarmellose sodium. Insome aspects, the disintegrant is croscarmellose sodium. In someaspects, the pharmaceutical composition comprises about 1 wt/wt % toabout 10 wt/wt % croscarmellose sodium. In some aspects, thepharmaceutical composition comprises about 3.5 wt/wt % to about 6 wt/wt% croscarmellose sodium. In some aspects, the pharmaceutical compositioncomprises about 1.0 wt/wt %, about 1.1 wt/wt %, about 1.2 wt/wt %, about1.3 wt/wt %, about 1.4 wt/wt %, about 1.5 wt/wt %, about 1.6 wt/wt %,about 1.7 wt/wt %, about 1.8 wt/wt %, about 1.9 wt/wt %, about 2.0 wt/wt%, about 2.1 wt/wt %, about 2.2 wt/wt %, about 2.3 wt/wt %, about 2.4wt/wt %, about 2.5 wt/wt %, about 2.6 wt/wt %, about 2.7 wt/wt %, about2.8 wt/wt %, about 2.9 wt/wt %, about 3.0 wt/wt %, about 3.1 wt/wt %,about 3.2 wt/wt %, about 3.3 wt/wt %, about 3.4 wt/wt %, about 3.5 wt/wt%, about 3.6 wt/wt %, about 3.7 wt/wt %, about 3.8 wt/wt %, about 3.9wt/wt %, about 4.0 wt/wt %, about 4.1 wt/wt %, about 4.2 wt/wt %, about4.3 wt/wt %, about 4.4 wt/wt %, about 4.5 wt/wt %, about 4.6 wt/wt %,about 4.7 wt/wt %, about 4.8 wt/wt %, about 4.9 wt/wt %, about 5 wt/wt%, about 5.1 wt/wt %, about 5.2 wt/wt %, about 5.3 wt/wt %, about 5.4wt/wt %, about 5.5 wt/wt %, about 5.6 wt/wt %, about 5.7 wt/wt %, about5.8 wt/wt %, about 5.9 wt/wt %, about 6.0 wt/wt %, about 6.1 wt/wt %,about 6.2 wt/wt %, about 6.3 wt/wt %, about 6.4 wt/wt %, about 76.5wt/wt %, about 6.6 wt/wt %, about 6.7 wt/wt %, about 6.8 wt/wt %, about6.9 wt/wt %, about 7.0 wt/wt %, about 7.1 wt/wt %, about 7.2 wt/wt %,about 7.3 wt/wt %, about 7.4 wt/wt %, about 7.5 wt/wt %, about 7.6 wt/wt%, about 7.7 wt/wt %, about 7.8 wt/wt %, about 7.9 wt/wt %, about 8.0wt/wt %, about 8.1 wt/wt %, about 8.2 wt/wt %, about 8.3 wt/wt %, about8.4 wt/wt %, about 8.5 wt/wt %, about 8.6 wt/wt %, about 8.7 wt/wt %,about 8.8 wt/wt %, about 8.9 wt/wt %, about 9.0 wt/wt %, about 9.1 wt/wt%, about 9.2 wt/wt %, about 9.3 wt/wt %, about 9.4 wt/wt %, about 9.5wt/wt %, about 9.6 wt/wt %, about 9.7 wt/wt %, about 9.8 wt/wt %, about9.9 wt/wt %, or about 10.0 wt/wt % croscarmellose sodium. In someaspects, the pharmaceutical composition comprises about 5 wt/wt %croscarmellose sodium.

In some aspects, the pharmaceutical composition comprises 0 wt/wt % toabout 5 wt/wt % of one or more lubricants. In some aspects, thepharmaceutical composition comprises about 0.1 wt/wt % to about 5 wt/wt% of one or more lubricants. In some aspects, the pharmaceuticalcomposition comprises 0 wt/wt % to about 2 wt/wt % of one or morelubricants. In some aspects, the pharmaceutical composition comprisesabout 0.1 wt/wt % to about 2 wt/wt % of one or more lubricants. In someaspects, the pharmaceutical composition comprises 0 wt/wt %, about 0.1wt/wt %, about 0.2 wt/wt %, about 0.3 wt/wt %, about 0.4 wt/wt %, about0.5 wt/wt %, about 0.6 wt/wt %, about 0.7 wt/wt %, about 0.8 wt/wt %,about 0.9 wt/wt %, about 1 wt/wt %, about 1.1 wt/wt %, about 1.2 wt/wt%, about 1.3 wt/wt %, about 1.4 wt/wt %, about 1.5 wt/wt %, about 1.6wt/wt %, about 1.7 wt/wt %, about 1.8 wt/wt %, about 1.9 wt/wt %, about2 wt/wt %, about 2.1 wt/wt %, about 2.2 wt/wt %, about 2.3 wt/wt %,about 2.4 wt/wt %, about 2.5 wt/wt %, about 2.6 wt/wt %, about 2.7 wt/wt%, about 2.8 wt/wt %, about 2.9 wt/wt %, about 3.0 wt/wt %, about 3.1wt/wt %, about 3.2 wt/wt %, about 3.3 wt/wt %, about 3.4 wt/wt %, about3.5 wt/wt %, about 3.6 wt/wt %, about 3.7 wt/wt %, about 3.8 wt/wt %,about 3.9 wt/wt %, about 4.0 wt/wt %, about 4.1 wt/wt %, about 4.2 wt/wt%, about 4.3 wt/wt %, about 4.4 wt/wt %, about 4.5 wt/wt %, about 4.6wt/wt %, about 4.7 wt/wt %, about 4.8 wt/wt %, about 4.9 wt/wt %, orabout 5.0 wt/wt % of one or more lubricants. In some aspects, thepharmaceutical composition comprises about 1 wt/wt % of one or morelubricants.

In some aspects, at least one of the lubricants is selected from thegroup consisting of magnesium stearate, sodium stearyl fumarate,glycerol dibehenate, stearic acid, hydrogenated vegetable oil, calciumstearate, zinc stearate, beeswax, colloidal silicon dioxide, and talc.In some aspects, at least one of the lubricants is magnesium stearate.In some aspects, the lubricant is magnesium stearate. In some aspects,the pharmaceutical composition comprises 0 wt/wt % to about 5 wt/wt % ofmagnesium stearate. In some aspects, the pharmaceutical compositioncomprises about 0.1 wt/wt % to about 5 wt/wt % of magnesium stearate. Insome aspects, the pharmaceutical composition comprises 0 wt/wt % toabout 2 wt/wt % of magnesium stearate. In some aspects, thepharmaceutical composition comprises about 0.1 wt/wt % to about 2 wt/wt% of magnesium stearate. In some aspects, the pharmaceutical compositioncomprises 0 wt/wt %, about 0.1 wt/wt %, about 0.2 wt/wt %, about 0.3wt/wt %, about 0.4 wt/wt %, about 0.5 wt/wt %, about 0.6 wt/wt %, about0.7 wt/wt %, about 0.8 wt/wt %, about 0.9 wt/wt %, about 1 wt/wt %,about 1.1 wt/wt %, about 1.2 wt/wt %, about 1.3 wt/wt %, about 1.4 wt/wt%, about 1.5 wt/wt %, about 1.6 wt/wt %, about 1.7 wt/wt %, about 1.8wt/wt %, about 1.9 wt/wt %, about 2 wt/wt %, about 2.1 wt/wt %, about2.2 wt/wt %, about 2.3 wt/wt %, about 2.4 wt/wt %, about 2.5 wt/wt %,about 2.6 wt/wt %, about 2.7 wt/wt %, about 2.8 wt/wt %, about 2.9 wt/wt%, about 3.0 wt/wt %, about 3.1 wt/wt %, about 3.2 wt/wt %, about 3.3wt/wt %, about 3.4 wt/wt %, about 3.5 wt/wt %, about 3.6 wt/wt %, about3.7 wt/wt %, about 3.8 wt/wt %, about 3.9 wt/wt %, about 4.0 wt/wt %,about 4.1 wt/wt %, about 4.2 wt/wt %, about 4.3 wt/wt %, about 4.4 wt/wt%, about 4.5 wt/wt %, about 4.6 wt/wt %, about 4.7 wt/wt %, about 4.8wt/wt %, about 4.9 wt/wt %, or about 5.0 wt/wt % magnesium stearate. Insome aspects, the pharmaceutical composition comprises 0 wt/wt %magnesium stearate. In some aspects, the pharmaceutical compositioncomprises about 0.1 wt/wt % magnesium stearate. In some aspects, thepharmaceutical composition comprises about 1 wt/wt % magnesium stearate.

In some aspects, the pharmaceutical composition comprises 0 wt/wt % toabout 5 wt/wt % of one or more flavoring agents. In some aspects, thepharmaceutical composition comprises 0 wt/wt % to about 2.5 wt/wt % ofone or more flavoring agents. In some aspects, the pharmaceuticalcomposition comprises 0 wt/wt %, about 0.1 wt/wt %, about 0.2 wt/wt %,about 0.3 wt/wt %, about 0.4 wt/wt %, about 0.5 wt/wt %, about 0.6 wt/wt%, about 0.7 wt/wt %, about 0.8 wt/wt %, about 0.9 wt/wt %, about 1wt/wt %, about 1.1 wt/wt %, about 1.2 wt/wt %, about 1.3 wt/wt %, about1.4 wt/wt %, about 1.5 wt/wt %, about 1.6 wt/wt %, about 1.7 wt/wt %,about 1.8 wt/wt %, about 1.9 wt/wt %, about 2 wt/wt %, about 2.1 wt/wt%, about 2.2 wt/wt %, about 2.3 wt/wt %, about 2.4 wt/wt %, about 2.5wt/wt %, about 2.6 wt/wt %, about 2.7 wt/wt %, about 2.8 wt/wt %, about2.9 wt/wt %, about 3.0 wt/wt %, about 3.1 wt/wt %, about 3.2 wt/wt %,about 3.3 wt/wt %, about 3.4 wt/wt %, about 3.5 wt/wt %, about 3.6 wt/wt%, about 3.7 wt/wt %, about 3.8 wt/wt %, about 3.9 wt/wt %, about 4.0wt/wt %, about 4.1 wt/wt %, about 4.2 wt/wt %, about 4.3 wt/wt %, about4.4 wt/wt %, about 4.5 wt/wt %, about 4.6 wt/wt %, about 4.7 wt/wt %,about 4.8 wt/wt %, about 4.9 wt/wt %, or about 5.0 wt/wt % of one ormore flavoring agents. In some aspects, the pharmaceutical compositioncomprises about 2 wt/wt % of one or more flavoring agents.

In some aspects, at least one of the flavoring agents is selected fromthe group consisting of natural or synthetic flavors including but notlimited to, grape flavoring, bubble gum flavoring, caramel flavoring,orange flavoring, lemon flavoring, strawberry flavoring, raspberryflavoring, mint flavoring, peppermint flavoring, grapefruit flavoring,pineapple flavoring, pear flavoring, peach flavoring, vanilla flavoring,banana flavoring, or cherry flavoring. In some aspects, at least one ofthe flavoring agents is grape flavoring. In some aspects, thepharmaceutical composition comprises 0 wt/wt % to about 5.0 wt/wt %grape flavoring. In some aspects, the pharmaceutical compositioncomprises 0 wt/wt % to about 2.5 wt/wt % grape flavoring. In someaspects, the pharmaceutical composition comprises 0 wt/wt %, about 0.1wt/wt %, about 0.2 wt/wt %, about 0.3 wt/wt %, about 0.4 wt/wt %, about0.5 wt/wt %, about 0.6 wt/wt %, about 0.7 wt/wt %, about 0.8 wt/wt %,about 0.9 wt/wt %, about 1 wt/wt %, about 1.1 wt/wt %, about 1.2 wt/wt%, about 1.3 wt/wt %, about 1.4 wt/wt %, about 1.5 wt/wt %, about 1.6wt/wt %, about 1.7 wt/wt %, about 1.8 wt/wt %, about 1.9 wt/wt %, about2 wt/wt %, about 2.1 wt/wt %, about 2.2 wt/wt %, about 2.3 wt/wt %,about 2.4 wt/wt %, about 2.5 wt/wt %, about 2.6 wt/wt %, about 2.7 wt/wt%, about 2.8 wt/wt %, about 2.9 wt/wt %, about 3.0 wt/wt %, about 3.1wt/wt %, about 3.2 wt/wt %, about 3.3 wt/wt %, about 3.4 wt/wt %, about3.5 wt/wt %, about 3.6 wt/wt %, about 3.7 wt/wt %, about 3.8 wt/wt %,about 3.9 wt/wt %, about 4.0 wt/wt %, about 4.1 wt/wt %, about 4.2 wt/wt%, about 4.3 wt/wt %, about 4.4 wt/wt %, about 4.5 wt/wt %, about 4.6wt/wt %, about 4.7 wt/wt %, about 4.8 wt/wt %, about 4.9 wt/wt %, orabout 5.0 wt/wt % grape flavoring. In some aspects, the pharmaceuticalcomposition comprises about 2 wt/wt % grape flavoring.

In some aspects, the pharmaceutical composition comprises 0 wt/wt % toabout 5 wt/wt % of one or more sweeteners. In some aspects, thepharmaceutical composition comprises 0 wt/wt % to about 2 wt/wt % of oneor more sweeteners. In some aspects, the pharmaceutical compositioncomprises 0 wt/wt %, about 0.1 wt/wt %, about 0.2 wt/wt %, about 0.3wt/wt %, about 0.4 wt/wt %, about 0.5 wt/wt %, about 0.6 wt/wt %, about0.7 wt/wt %, about 0.8 wt/wt %, about 0.9 wt/wt %, about 1 wt/wt %,about 1.1 wt/wt %, about 1.2 wt/wt %, about 1.3 wt/wt %, about 1.4 wt/wt%, about 1.5 wt/wt %, about 1.6 wt/wt %, about 1.7 wt/wt %, about 1.8wt/wt %, about 1.9 wt/wt %, about 2 wt/wt %, about 2.1 wt/wt %, about2.2 wt/wt %, about 2.3 wt/wt %, about 2.4 wt/wt %, about 2.5 wt/wt %,about 2.6 wt/wt %, about 2.7 wt/wt %, about 2.8 wt/wt %, about 2.9 wt/wt%, about 3.0 wt/wt %, about 3.1 wt/wt %, about 3.2 wt/wt %, about 3.3wt/wt %, about 3.4 wt/wt %, about 3.5 wt/wt %, about 3.6 wt/wt %, about3.7 wt/wt %, about 3.8 wt/wt %, about 3.9 wt/wt %, about 4.0 wt/wt %,about 4.1 wt/wt %, about 4.2 wt/wt %, about 4.3 wt/wt %, about 4.4 wt/wt%, about 4.5 wt/wt %, about 4.6 wt/wt %, about 4.7 wt/wt %, about 4.8wt/wt %, about 4.9 wt/wt %, or about 5.0 wt/wt % of one or moresweeteners. In some aspects, the pharmaceutical composition comprisesabout 1 wt/wt % of one or more sweeteners.

In some aspects, at least one of the sweeteners is selected from thegroup consisting of sucralose, acesulfame, saccharin, sucrose, xylitol,mannitol, sorbitol, glucose, fructose, and aspartame. In some aspects,at least one of the sweeteners is sucralose. In some aspects, thesweetener is sucralose. In some aspects, the pharmaceutical compositioncomprises 0 wt/wt % to about 5 wt/wt % sucralose. In some aspects, thepharmaceutical composition comprises 0 wt/wt % to about 2 wt/wt %sucralose. In some aspects, the pharmaceutical composition comprises 0wt/wt %, about 0.1 wt/wt %, about 0.2 wt/wt %, about 0.3 wt/wt %, about0.4 wt/wt %, about 0.5 wt/wt %, about 0.6 wt/wt %, about 0.7 wt/wt %,about 0.8 wt/wt %, about 0.9 wt/wt %, about 1 wt/wt %, about 1.1 wt/wt%, about 1.2 wt/wt %, about 1.3 wt/wt %, about 1.4 wt/wt %, about 1.5wt/wt %, 1.6 wt/wt %, about 1.7 wt/wt %, about 1.8 wt/wt %, about 1.9wt/wt %, about 2 wt/wt %, about 2.1 wt/wt %, about 2.2 wt/wt %, about2.3 wt/wt %, about 2.4 wt/wt %, about 2.5 wt/wt %, about 2.6 wt/wt %,about 2.7 wt/wt %, about 2.8 wt/wt %, about 2.9 wt/wt %, about 3.0 wt/wt%, about 3.1 wt/wt %, about 3.2 wt/wt %, about 3.3 wt/wt %, about 3.4wt/wt %, about 3.5 wt/wt %, about 3.6 wt/wt %, about 3.7 wt/wt %, about3.8 wt/wt %, about 3.9 wt/wt %, about 4.0 wt/wt %, about 4.1 wt/wt %,about 4.2 wt/wt %, about 4.3 wt/wt %, about 4.4 wt/wt %, about 4.5 wt/wt%, about 4.6 wt/wt %, about 4.7 wt/wt %, about 4.8 wt/wt %, about 4.9wt/wt %, or about 5.0 wt/wt % sucralose. In some aspects, thepharmaceutical composition comprises about 1 wt/wt % sucralose.

In some aspects, the pharmaceutical composition is a capsule. In someaspects, the capsule comprises about 1 mg of one or more crystalline oramorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the capsule is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more lubricants; and (e) a gelatincapsule which encapsulates components (a)-(d).

In some aspects, the capsule comprises about 1 mg of one or morecrystalline or amorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the capsule is as follows: (a) about 0.25wt/wt % to about 1.5 wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d)about 0.5 wt/wt % to about 2 wt/wt % of one or more lubricants; and (e)a gelatin capsule which encapsulates components (a)-(d).

In some aspects, the capsule comprises about 2 mg of one or morecrystalline or amorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the capsule is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more lubricants; and (e) a gelatincapsule which encapsulates components (a)-(d).

In some aspects, the capsule comprises about 2 mg of one or morecrystalline or amorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the capsule is as follows: (a) about 0.25wt/wt % to about 1.5 wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d)about 0.5 wt/wt % to about 2 wt/wt % of one or more lubricants; and (e)a gelatin capsule which encapsulates components (a)-(d). In someaspects, the capsule comprises about 3 mg of one or more crystalline oramorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, wherein each component of the capsule is as follows:(a) about 0.1 wt/wt % to about 7 wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more lubricants; and (e) a gelatincapsule which encapsulates components (a)-(d).

In some aspects, the capsule comprises about 3 mg of one or morecrystalline or amorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, wherein each component of the capsule is as follows.(a) about 0.25 wt/wt % to about 1.5 wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d)about 0.5 wt/wt % to about 2 wt/wt % of one or more lubricants; and (e)a gelatin capsule which encapsulates components (a)-(d). In someaspects, the capsule comprises about 4 mg of one or more crystalline oramorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the capsule is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more lubricants; and (e) a gelatincapsule which encapsulates components (a)-(d).

In some aspects, the capsule comprises about 4 mg of one or morecrystalline or amorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the capsule is as follows: (a) about 0.25wt/wt % to about 1.5 wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d)about 0.5 wt/wt % to about 2 wt/wt % of one or more lubricants; and (e)a gelatin capsule which encapsulates components (a)-(d).

In some aspects, the capsule comprises about 5 mg of one or morecrystalline or amorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the capsule is as follows: (a) about 2.5 wt/wt% to about 7.0 wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; and(d) a gelatin capsule which encapsulates components (a)-(c).

In some aspects, the capsule comprises about 5 mg of one or morecrystalline or amorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the capsule is as follows: (a) about 2.5 wt/wt% to about 7.0 wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; and(d) a gelatin capsule which encapsulates components (a)-(c).

In some aspects, the pharmaceutical composition is a tablet (e.g.,dispersible tablet). In some aspects, the tablet is a dispersibletablet. In some aspects, the tablet (e.g., dispersible tablet) comprisesabout 0.5 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the tablet (e.g.,dispersible tablet) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the tablet (e.g., dispersible tablet) comprises about0.5 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the tablet (e.g.,dispersible tablet) is as follows: (a) about 0.5 wt/wt % to about 1.2wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the tablet (e.g., dispersible tablet) comprises about 1mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the tablet (e.g.,dispersible tablet) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the tablet (e.g., dispersible tablet) comprises about 1mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the tablet (e.g.,dispersible tablet) is as follows: (a) about 0.5 wt/wt % to about 1.2wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the tablet (e.g., dispersible tablet) comprises about 2mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the tablet (e.g.,dispersible tablet) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the tablet (e.g., dispersible tablet) comprises about 2mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the tablet (e.g.,dispersible tablet) is as follows: (a) about 0.5 wt/wt % to about 1.2wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the tablet (e.g., dispersible tablet) comprises about 3mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the tablet (e.g.,dispersible tablet) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the tablet (e.g., dispersible tablet) comprises about 3mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the tablet (e.g.,dispersible tablet) is as follows: (a) about 0.5 wt/wt % to about 1.2wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the tablet (e.g., dispersible tablet) comprises about 4mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the tablet (e.g.,dispersible tablet) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the tablet (e.g., dispersible tablet) comprises about 4mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the tablet (e.g.,dispersible tablet) is as follows: (a) about 0.5 wt/wt % to about 1.2wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the tablet (e.g., dispersible tablet) comprises about 5mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the tablet (e.g.,dispersible tablet) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the tablet (e.g., dispersible tablet) comprises about 5mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the tablet (e.g.,dispersible tablet) is as follows: (a) about 0.5 wt/wt % to about 1.2wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the tablet (e.g., dispersible tablet) comprises about0.1 mg to about 5 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;wherein the pharmaceutical composition is dispersible in a potableliquid; and wherein each component of the pharmaceutical composition isas follows: (a) about 0.1 wt/wt % to about 7 wt/wt % of a crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the tablet (e.g., dispersible tablet) comprises about0.1 mg to about 5 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;wherein the pharmaceutical composition is dispersible in a potableliquid; and wherein each component of the pharmaceutical composition isas follows: (a) about 0.5 wt/wt % to about 1.2 wt/wt % of a crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the tablet (e.g., dispersible tablet) is dissolved in apotable liquid before administration. In some aspects, the potableliquid is water, milk or a juice (e.g., orange juice or apple juice). Insome aspects, the potable liquid is water. In some aspects, the potableliquid is a juice. In some aspects, the tablet is orodispersible in asubject's saliva.

In some aspects, the pharmaceutical composition is a powder (e.g.,dispersible powder). In some aspects, the powder (e.g., dispersiblepowder) is a dispersible powder. In some aspects, a capsule or sachetcomprises the dispersible powder. In some aspects, the powder (e.g.,dispersible powder) comprises about 0.5 mg of a crystalline or amorphousform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the powder (e.g.,dispersible powder) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the powder (e.g., dispersible powder) comprises about0.5 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the powder (e.g.,dispersible powder) is as follows: (a) about 0.5 wt/wt % to about 1.2wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the powder (e.g., dispersible powder) comprises about 1mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the powder (e.g.,dispersible powder) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the powder (e.g., dispersible powder) comprises about 1mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the powder (e.g.,dispersible powder) is as follows: (a) about 0.5 wt/wt % to about 1.2wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the powder (e.g., dispersible powder) comprises about 2mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the powder (e.g.,dispersible powder) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the powder (e.g., dispersible powder) comprises about 2mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the powder (e.g.,dispersible powder) is as follows: (a) about 0.5 wt/wt % to about 1.2wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the powder (e.g., dispersible powder) comprises about 3mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the powder (e.g.,dispersible powder) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the powder (e.g., dispersible powder) comprises about 3mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the powder (e.g.,dispersible powder) is as follows: (a) about 0.5 wt/wt % to about 1.2wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the powder (e.g., dispersible powder) comprises about 4mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the powder (e.g.,dispersible powder) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the powder (e.g., dispersible powder) comprises about 4mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the powder (e.g.,dispersible powder) is as follows: (a) about 0.5 wt/wt % to about 1.2wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the powder (e.g., dispersible powder) comprises about 5mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the powder (e.g.,dispersible powder) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the powder (e.g., dispersible powder) comprises about 5mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the powder (e.g.,dispersible powder) is as follows: (a) about 0.5 wt/wt % to about 1.2wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the powder (e.g., dispersible powder) comprises about0.1 mg to about 5 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;wherein the pharmaceutical composition is dispersible in a potableliquid; and wherein each component of the pharmaceutical composition isas follows: (a) about 0.1 wt/wt % to about 7 wt/wt % of a crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the powder (e.g., dispersible powder) comprises about0.1 mg to about 5 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;wherein the pharmaceutical composition is dispersible in a potableliquid; and wherein each component of the pharmaceutical composition isas follows: (a) about 0.5 wt/wt % to about 1.2 wt/wt % of a crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the powder (e.g., dispersible powder) is dissolved in apotable liquid before administration. In some aspects, the potableliquid is water, milk or a juice (e.g., orange juice or apple juice). Insome aspects, the potable liquid is water. In some aspects, the potableliquid is a juice. In some aspects, the powder is orodispersible in asubject's saliva.

In some aspects, the pharmaceutical composition is in the form ofgranules (e.g., dispersible granules). In some aspects, the granules(e.g., dispersible granules) are dispersible granules. In some aspects,a capsule or sachet comprises the dispersible granules. In some aspects,the granules (e.g., dispersible granules) comprise about 0.5 mg of acrystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the granules (e.g.,dispersible granules) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the granules (e.g., dispersible granules) compriseabout 0.5 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the granules (e.g.,dispersible granules) is as follows. (a) about 0.5 wt/wt % to about 1.2wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the granules (e.g., dispersible granules) compriseabout 1 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the granules (e.g.,dispersible granules) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the granules (e.g., dispersible granules) compriseabout 1 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the granules (e.g.,dispersible granules) is as follows: (a) about 0.5 wt/wt % to about 1.2wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the granules (e.g., dispersible granules) compriseabout 2 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the granules (e.g.,dispersible granules) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the granules (e.g., dispersible granules) compriseabout 2 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the granules (e.g.,dispersible granules) is as follows: (a) about 0.5 wt/wt % to about 1.2wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the granules (e.g., dispersible granules) compriseabout 3 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the granules (e.g.,dispersible granules) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the granules (e.g., dispersible granules) compriseabout 3 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the granules (e.g.,dispersible granules) is as follows: (a) about 0.5 wt/wt % to about 1.2wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the granules (e.g., dispersible granules) compriseabout 4 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the granules (e.g.,dispersible granules) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the granules (e.g., dispersible granules) compriseabout 4 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the granules (e.g.,dispersible granules) is as follows: (a) about 0.5 wt/wt % to about 1.2wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the granules (e.g., dispersible granules) compriseabout 5 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the granules (e.g.,dispersible granules) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the granules (e.g., dispersible granules) compriseabout 5 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the granules (e.g.,dispersible granules) is as follows: (a) about 0.5 wt/wt % to about 1.2wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the granules (e.g., dispersible granules) compriseabout 0.1 mg to about 5 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;wherein the pharmaceutical composition is dispersible in a potableliquid; and wherein each component of the pharmaceutical composition isas follows: (a) about 0.1 wt/wt % to about 7 wt/wt % of a crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the granules (e.g., dispersible granules) compriseabout 0.1 mg to about 5 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;wherein the pharmaceutical composition is dispersible in a potableliquid; and wherein each component of the pharmaceutical composition isas follows: (a) about 0.5 wt/wt % to about 1.2 wt/wt % of a crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the granules (e.g., dispersible granules) are dissolvedin a potable liquid before administration. In some aspects, the potableliquid is water, milk or a juice (e.g., orange juice or apple juice). Insome aspects, the potable liquid is water. In some aspects, the potableliquid is a juice. In some aspects, the granules are orodispersible in asubject's saliva.

In some aspects, the pharmaceutical composition is in the form ofminitablets (e.g., dispersible minitablets). In some aspects, theminitablets are dispersible minitablets. In some aspects, theminitablets (e.g., dispersible minitablets) comprise about 0.5 mg of acrystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the minitablets (e.g.,dispersible minitablets) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the minitablets (e.g., dispersible minitablets)comprise about 0.5 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the minitablets (e.g.,dispersible minitablets) is as follows: (a) about 0.5 wt/wt %4 to about1.2 wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the minitablets (e.g., dispersible minitablets)comprise about 1 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the minitablets (e.g.,dispersible minitablets) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the minitablets (e.g., dispersible minitablets)comprise about 1 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the minitablets (e.g.,dispersible minitablets) is as follows: (a) about 0.5 wt/wt % to about1.2 wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the minitablets (e.g., dispersible minitablets)comprise about 2 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the minitablets (e.g.,dispersible minitablets) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the minitablets (e.g., dispersible minitablets)comprise about 2 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the minitablets (e.g.,dispersible minitablets) is as follows: (a) about 0.5 wt/wt % to about1.2 wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the minitablets (e.g., dispersible minitablets)comprise about 3 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the minitablets (e.g.,dispersible minitablets) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the minitablets (e.g., dispersible minitablets)comprise about 3 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the minitablets (e.g.,dispersible minitablets) is as follows: (a) about 0.5 wt/wt % to about1.2 wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the minitablets (e.g., dispersible minitablets)comprise about 4 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the minitablets (e.g.,dispersible minitablets) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the minitablets (e.g., dispersible minitablets)comprise about 4 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the minitablets (e.g.,dispersible minitablets) is as follows: (a) about 0.5 wt/wt % to about1.2 wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the minitablets (e.g., dispersible minitablets)comprise about 5 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the minitablets (e.g.,dispersible minitablets) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the minitablets (e.g., dispersible minitablets)comprise about 5 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the minitablets (e.g.,dispersible minitablets) is as follows: (a) about 0.5 wt/wt % to about1.2 wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the minitablets (e.g., dispersible minitablets)comprise about 0.1 mg to about 5 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;wherein the pharmaceutical composition is dispersible in a potableliquid; and wherein each component of the pharmaceutical composition isas follows: (a) about 0.1 wt/wt % to about 7 wt/wt % of a crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the minitablets (e.g., dispersible minitablets)comprise about 0.1 mg to about 5 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;wherein the pharmaceutical composition is dispersible in a potableliquid; and wherein each component of the pharmaceutical composition isas follows: (a) about 0.5 wt/wt % to about 1.2 wt/wt % of a crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the minitablets (e.g., dispersible minitablets) aredissolved in a potable liquid before administration. In some aspects,the potable liquid is water, milk or a juice (e.g., orange juice orapple juice). In some aspects, the potable liquid is water. In someaspects, the potable liquid is a juice. In some aspects, the minitabletsare orodispersible in a subject's saliva.

In some aspects, the pharmaceutical composition is in the form ofpellets (e.g., dispersible pellet). In some aspects, the pellets aredispersible pellets. In some aspects, the pellets (e.g., dispersiblepellets) comprise about 0.5 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the pellets (e.g.,dispersible pellets) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the pellets (e.g., dispersible pellets) comprise about0.5 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the pellets (e.g.,dispersible pellets) is as follows: (a) about 0.5 wt/wt % to about 1.2wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the pellets (e.g., dispersible pellets) comprise about1 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the pellets (e.g.,dispersible pellets) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the pellets (e.g., dispersible pellets) comprise about1 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the pellets (e.g.,dispersible pellets) is as follows: (a) about 0.5 wt/wt % to about 1.2wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the pellets (e.g., dispersible pellets) comprise about2 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the pellets (e.g.,dispersible pellets) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the pellets (e.g., dispersible pellets) comprise about2 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the pellets (e.g.,dispersible pellets) is as follows: (a) about 0.5 wt/wt % to about 1.2wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the pellets (e.g., dispersible pellets) comprise about3 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the pellets (e.g.,dispersible pellets) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the pellets (e.g., dispersible pellets) comprise about3 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the pellets (e.g.,dispersible pellets) is as follows: (a) about 0.5 wt/wt % to about 1.2wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the pellets (e.g., dispersible pellets) comprise about4 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the pellets (e.g.,dispersible pellets) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the pellets (e.g., dispersible pellets) comprise about4 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the pellets (e.g.,dispersible pellets) is as follows: (a) about 0.5 wt/wt % to about 1.2wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the pellets (e.g., dispersible pellets) comprise about5 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the pellets (e.g.,dispersible pellets) is as follows: (a) about 0.1 wt/wt % to about 7wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the pellets (e.g., dispersible pellets) comprise about5 mg of a crystalline or amorphous form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein, and wherein each component of the pellets (e.g.,dispersible pellets) is as follows: (a) about 0.5 wt/wt % to about 1.2wt/wt % of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the pellets (e.g., dispersible pellets) comprise about0.1 mg to about 5 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;wherein the pharmaceutical composition is dispersible in a potableliquid, and wherein each component of the pharmaceutical composition isas follows: (a) about 0.1 wt/wt % to about 7 wt/wt % of a crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents; (c)about 1 wt/wt % to about 10 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 5 wt/wt % of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt % of one or more sweeteners; and (f) 0 wt/wt % toabout 5 wt/wt % of one or more lubricants.

In some aspects, the pellets (e.g., dispersible pellets) comprise about0.1 mg to about 5 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;wherein the pharmaceutical composition is dispersible in a potableliquid; and wherein each component of the pharmaceutical composition isas follows: (a) about 0.5 wt/wt % to about 1.2 wt/wt % of a crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) 0wt/wt % to about 2.5 wt/wt % of one or more flavoring agents; (e) 0wt/wt % to about 2 wt/wt % of one or more sweeteners; and (f) about 0.5wt/wt % to about 2 wt/wt % of one or more lubricants.

In some aspects, the pellets (e.g., dispersible pellets) are dissolvedin a potable liquid before administration. In some aspects, the potableliquid is water, milk or a juice (e.g., orange juice or apple juice). Insome aspects, the potable liquid is water. In some aspects, the potableliquid is a juice. In some aspects, the pellets are orodispersible in asubject's saliva.

Methods of Treatment

In some aspects, the present disclosure provides a method of treating atumor, a cancer, or a Rasopathy disorder comprising administering to asubject in need of such treatment a pharmaceutical composition describedherein.

In some aspects, the tumor is a neurofibroma. In some aspects, the tumoris a neurofibroma associated with Neurofibromatosis Type 1. In someaspects, the tumor is selected from the group consisting of cutaneousneurofibroma, plexiform neurofibroma, optic pathway glioma, low gradeglioma, high grade glioma, or malignant peripheral nerve sheath tumor.In some aspects, the tumor is plexiform neurofibroma.

In some aspects, the subject has been diagnosed with a Rasopathydisorder selected from the group consisting of neurofibromatosis type 1,neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costellosyndrome, Legius syndrome, Noonan syndrome, and Noonan syndrome withmultiple lentigines.

In some aspects, the cancer is selected from the group consisting ofskin cancer, malignant peripheral nerve sheath cancer, leukemia,lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovariancancer, renal cancer, colorectal cancer, thyroid cancer,cholangiocarcinoma, urothelial cancer, uterine neoplasm, gastric cancer,sarcoma, bladder cancer, head and neck cancer, endometrial cancer,esophageal cancer, adenoid cystic carcinoma, gallbladder cancer,prostate cancer, oral cancer, cervical cancer, pancreatic cancer,melanoma, hepatocellular cancer, biliary tract cancer, and serouscarcinoma of the peritoneum. In some aspects, the leukemia is selectedfrom the group consisting of acute lymphocytic leukemia, acutemyelogenous leukemia, chronic lymphocytic leukemia, and chronicmyelogenous leukemia. In some aspects, the lymphoma is selected from thegroup consisting of B-cell lymphoma, T-cell lymphoma, Burkitt'slymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinalB cell lymphoma, small lymphocytic lymphoma, and Waldenstrommacroglobulinemia. In some aspects, the lung cancer is selected from thegroup consisting of lung adenocarcinoma, squamous non-small cell lungcancer, non-squamous non-small cell lung cancer, and small cell lungcancer.

In some aspects, the subject bears a mutation or other aberration in oneor more genes for which the mutation or other aberration causes a gainor loss of function characteristic of certain cancers, wherein themutation or other aberration in one or more genes is a mutation or otheraberration in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1,MAP2K4, NF1, or NF2.

In some aspects, an individual dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered as more than one capsule, tablet (e.g., dispersibletablet), dose of powder (e.g., dispersible powder), dose of granules(e.g., dispersible granules), dose of minitablets (e.g., dispersibleminitablets), dose of pellets (e.g., dispersible pellets), or acombination thereof. For example, a dose of 3 mg of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecan be administered as two capsules—one containing 2 mg and the othercontaining 1 mg or as three capsules each containing 1 mg. As anotherexample, a dose of 1.5 mg of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecan be administered as two dispersible dosage forms—one dispersibletablet containing 1 mg and a separate unit of dispersible powdercontaining 0.5 mg or as three units of dispersible powder eachcontaining 0.5 mg.

In some aspects, if theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis to be administered more than one time a day, the total daily dose oftheN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecan be divided so the patient receives different doses at eachadministration. For example, if the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis to be 2 mg administered two times per day, the patient can receive0.5 mg (e.g., as one 0.5 mg tablet (e.g., dispersible tablet)) in themorning and 1.5 mg (e.g., as one 0.5 mg dose of powder (e.g.,dispersible powder) and one 1 mg capsule) in the evening.

In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis provided in an amount of about 0.1 mg to about 20 mg per dose of thepharmaceutical compositions described herein. In some aspects, one ormore crystalline or amorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis provided in an amount of about 0.1 mg, about 0.2 mg, about 0.3 mg,about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg,about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg,about 17 mg, about 18 mg, about 19 mg, or about 20 mg per dose. In someaspects, one or more crystalline or amorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis provided in an amount of about 0.5 mg per dose. In some aspects, oneor more crystalline or amorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis provided in an amount of about 1 mg per dose. In some aspects, one ormore crystalline or amorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis provided in an amount of about 2 mg per dose. In some aspects, one ormore crystalline or amorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis provided in an amount of about 3 mg per dose. In some aspects, one ormore crystalline or amorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis provided in an amount of about 4 mg per dose. In some aspects, one ormore crystalline or amorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis provided in an amount of about 5 mg per dose. In some aspects, one ormore crystalline or amorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis provided in an amount of about 10 mg per dose. In some aspects, oneor more crystalline or amorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis provided in an amount of about 20 mg per dose.

In some aspects, the pharmaceutical composition comprising one or morecrystalline or amorphous forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered one time, two times, three times, or four times per day.In some aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times per day.

In some aspects, the present disclosure provides a method of treating atumor, a cancer, or a Rasopathy disorder comprising administering to apatient in need of such treatment a pharmaceutical composition describedherein, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily of about 0.1 mg to about 10 mg each.

In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered via a pharmaceutical composition described herein,wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis provided at a total daily dose that does not exceed 0.5 mg, 1 mg, 2mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg. In some aspects,theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 20 mg. Insome aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 15 mg. Insome aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 12 mg. Insome aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 10 mg. Insome aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 8 mg. In someaspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 6 mg. In someaspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 4 mg. In someaspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 2 mg. In someaspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 1 mg.

In some aspects, the present disclosure provides a method of treating atumor, a cancer, or a Rasopathy disorder comprising administering to apatient in need of such treatment a pharmaceutical composition describedherein, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 0.1 mg to about 20 mg.

In some aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily. In some aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 0.1 mg to about 20 mg. Insome aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 0.1 mg, about 0.2 mg,about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg,about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg,about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg. Insome aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 0.5 mg. In some aspects,the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 1 mg. In some aspects, thetotal daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 2 mg. In some aspects, thetotal daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 3 mg. In some aspects, thetotal daily dose ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 4 mg. In some aspects, thetotal daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 5 mg. In some aspects, thetotal daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 6 mg. In some aspects, thetotal daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 7 mg. In some aspects, thetotal daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 8 mg. In some aspects, thetotal daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 9 mg. In some aspects, thetotal daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 10 mg. In some aspects,the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 11 mg. In some aspects,the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 12 mg. In some aspects,the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 13 mg. In some aspects,the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 14 mg. In some aspects,the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 15 mg. In some aspects,the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 16 mg. In some aspects,the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 17 mg. In some aspects,the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 18 mg. In some aspects,the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 19 mg. In some aspects,the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 20 mg.

In some aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily. In some aspects, the total daily doseof theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 0.1 mg to about 10 mgeach. In some aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 0.1 mg, about 0.2 mg,about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg,about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about10 mg each. In some aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 0.25 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 0.5 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 1 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 2 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 3 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 4 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 5 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 6 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 7 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 8 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 9 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 10 mg each.

In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) 21 days inwhich the total daily dose is administered; and (b) 7 days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered. In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) 21 consecutivedays in which the total daily dose is administered; followed by (b) 7consecutive days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered.

In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) three 7-dayperiods each comprising (i) 5 days in which the total daily dose isadministered and (ii) 2 days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;and (b) 7 days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered. In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) three 7-dayperiods each comprising (i) 5 consecutive days in which the total dailydose is administered and (ii) 2 consecutive days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;followed by (b) 7 consecutive days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered.

In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising 28 days in which thetotal daily dose is administered.

In some aspects, the 28-day dosing cycle is repeated up to a total of 24consecutive 28-day dosing cycles.

In some aspects, the pharmaceutical composition is a dispersible tablet,dispersible powder, dispersible granules, dispersible minitablets, ordispersible pellets, and wherein the pharmaceutical composition isdispersed in a potable liquid (e.g., water or a juice (e.g., orangejuice or apple juice)) prior to administration to the subject.

In some aspects, the composition is an orodispersible dosage form (e.g.,dispersible tablet, dispersible powder, dispersible granules,dispersible minitablets, or dispersible pellets) which is administeredto the subject without first dissolving the dosage form in a separatecontainer.

In some aspects, the subject experiences dysphagia. In some aspects, thesubject experiences dysphagia caused by one or more of: disease of thenervous system, muscle weakening, developmental disability, stroke,injury, anatomical defect, cancer, treatment for cancer, allergicreaction, dementia, memory loss, or cognitive decline. In some aspects,the subject has been diagnosed with an autism spectrum disorder. In someaspects, the subject has been diagnosed with a craniofacial disorder. Insome aspects, the subject has been diagnosed with myasthenia gravis. Insome aspects, the subject has been diagnosed with tardive dyskinesia.

In some aspects, the subject is a pediatric subject. In some aspects,the subject is less than 18 years old, less than 17 years old, less than16 years old, less than 15 years old, less than 14 years old, less than13 years old, less than 12 years old, less than 11 years old, less than10 years old, less than 9 years old, less than 8 years old, less than 7years old, less than 6 years old, less than 5 years old, less than 4years old, less than 3 years old, less than 2 years old, or less than 1year old. In some aspects, the subject is 1 year old, 2 years old, 3years old, 4 years old, 5 years old, 6 years old, 7 years old, 8 yearsold, 9 years old, 10 years old, 11 years old, 12 years old, 13 yearsold, 14 years old, 15 years old, 16 years old, or 17 years old. In someaspects, the subject is less than 13 years old. In some aspects, thesubject is less than 12 years old. In some aspects, the subject is lessthan 11 years old. In some aspects, the subject is less than 10 yearsold. In some aspects, the subject is less than 9 years old. In someaspects, the subject is less than 8 years old. In some aspects, thesubject is less than 7 years old. In some aspects, the subject is lessthan 6 years old. In some aspects, the subject is less than 5 years old.In some aspects, the subject is less than 4 years old. In some aspects,the subject is less than 3 years old. In some aspects, the subject isless than 2 years old. In some aspects, the subject is less than 1 yearold. In some aspects, the subject is about 2 to about 18 years old. Insome aspects, the subject is about 3 to about 17 years old. In someaspects, the subject is about 4 to about 16 years old. In some aspects,the subject is about 5 to about 15 years old. In some aspects, thesubject is about 6 to about 14 years old. In some aspects, the subjectis about 7 to about 13 years old. In some aspects, the subject is about8 to about 12 years old.

In some aspects, the subject is a geriatric subject. In some aspects,the subject is more than 30 years old, more than 35 years old, more than40 years old, more than 45 years old, more than 50 years old, more than55 years old, more than 60 years old, more than 65 years old, more than70 years old, more than 75 years old, more than 80 years old, more than85 years old, more than 90 years old, more than 95 years old, or morethan 100 year old. In some aspects, the subject is more than 50 yearsold. In some aspects, the subject is more than 60 years old. In someaspects, the subject is more than 70 years old. In some aspects, thesubject is more than 80 years old. In some aspects, the subject is morethan 90 years old. In some aspects, the subject is more than 100 yearsold.

In some aspects, the present disclosure provides use of a pharmaceuticalcomposition described herein for the manufacture of a medicament fortreating a cancer, a tumor, or a Rasopathy disorder.

Methods of PreparingN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideand Essentially Pure Form IV

Novel methods of producingN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideof Formula (I)

that comprise reacting PD-0315209 (FIPFA) and PD-0337792 (IPGA) with acoupling reagent that is 1-propylphosphonic anhydride (“T3P”) to obtain901 Acetonide, as shown in Scheme I below, are disclosed herein.

In some aspects, the T3P is in solution. In some aspects, T3P isprovided as a solution in ethyl acetate.

In some aspects, the method of producing essentially pure Form IVN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideof Formula (I) comprises (a) reacting PD-0315209 (FIPFA) and PD-0337792(IPGA) with a coupling reagent that is T3P to obtain 901 Acetonide; and(b) treating 901 Acetonide with acid to formN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,as shown in Scheme II below.

In some aspects, the synthesis for essentially pure crystalline Form IVofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideof Formula (I) comprises the reaction set forth according to Scheme III.

In some aspects, the synthesis for essentially pure Form IV ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideof Formula (I) is as shown below in Scheme IV.

In some aspects, the methods of preparingN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideyields a crystalline composition that is essentially pure Form IV ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

In some aspects, the essentially pure Form IV crystalline compositioncontains ≤0.2% of dimeric impurity PF-00191189

In some aspects, the essentially pure Form IV crystalline compositioncontains about 0.05% to about 0.19% by weight of dimeric impurityPF-00191189. In some aspects, the essentially pure Form IV crystallinecomposition contains about 0.05% to about 0.15% by weight of dimericimpurity PF-00191189. In some aspects, the essentially pure Form IVcrystalline composition contains about 0.05% to about 0.10% by weight ofdimeric impurity PF-00191189. In some aspects, the essentially pure FormIV crystalline composition contains no detectable amount of dimericimpurity PF-00191189.

In some aspects, the amount of dimeric impurity PF-00191189 isdetermined using High Performance Liquid Chromatography (“HPLC”). Insome aspects, reversed-phase liquid chromatography using an ultravioletdetector at 275 nm is used.

EXAMPLES

Abbreviations and Acronyms

ACN Acetonitrile CC Controlled cooling DCM Dichloromethane DMFN,N-Dimethyl formamide DMSO Dimethyl sulfoxide DSC Differential scanningcalorimetry EtOAc Ethyl acetate EtOH Ethanol Exp Experiment FEV Fastevaporation FIA 2-fluoro-4-idodoaniline FT Fourier Transform GVSGravimetric Vapor Sorption HCI Hydrochloric acid HOAc Acetic acidi-Pr₂NEt N,N-diisopropylethylamine IPA 2-Propanol IPE Isopropyl etherLiNH₂ Lithium amide MeCN Acetonitrile MeOH Methanol MIBK4-Methyl-2-pentanone min Minutes MTBE Methyl t-butyl ether n/a NotApplicable NaOH Sodium hydroxide NH₄OH Ammonium hydroxide NHPN-hydroxyphthalimide PLM Polarized light microscopy PXRD Powder X-raydiffraction (also known as XRPD (X-ray powder diffraction) RC Rapidcooling RT Room temperature SAS Solvent-antisolvent SEV Slow evaporationSGA (S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol SU Scale Up t-BuOHTert-butanol TC Temperature cycling T3P 1-propylphosphonic anhydridesolution TEA triethylamine Tf₂O Trifluoromethanesulfonic anhydride TFBA2,3,4-trifluorobenzoic acid TFE 2,2,2-Trifluoroethanol TGAThermogravimetric analyzer TGA-IR Thermogravimetric analysis interfacedwith infrared spectrophotometer THF Tetrahydrofuran v/v Volume/volume

Example 1: Production of Seed Crystals of Form V

Step 1: Preparation of “Side Chain”, PD-0337792

14.4 kg alcohol (chemical purity 99.4%, optical purity 99.6%enantiomeric excess) was converted to 97.5 kg 9.7% w/w PD-0337792 (IPGA)solution in toluene (overall yield ˜60%). The triflate activation wasperformed in the 200 L reactor by maintaining temperatures under −20° C.during triflic anhydride addition. The resulting activated alcohol wasthen transferred to a 400 L reactor containing solid N-hydroxypthalimide(NHP) and the reaction was allowed to occur at ambient temperature tocompletion. The final base de-protection was performed by adding aqueousammonia (˜28% soln, 5 equiv., 34 kg). After reaction completion, waterwas removed by distillation from toluene, and the resulting solid sideproduct was filtered out to yield the product solution.

Step 2: Preparation of PD-0315209

The process yielded 21.4 kg (99.4% w/w assay), which is 80% oftheoretical from starting materials 2,3,4-trifluorobenzoic acid (12 kg,1 eq.) and 2-fluoro-4-iodoaniline (16.4 kg, 1.02 eq.) with lithium amidebase (5 kg, 3.2 eq.). The reaction was initiated by adding 5% of totalsolution of TFBA and FIA into lithium amide slurry at 50° C. Thisreaction demonstrated a minimal initiation period of ˜10 minutes, whichwas observed by color change and slight exotherm. The remaining TFBA/FIAsolution in THF was slowly added through a pressure can in an hour whilemaintaining the reaction temperatures within 45-55° C. There was noappreciable pressure rise (due to ammonia gas release) observed duringthe entire operation.

Step 3: Preparation of PD-0325901

A modification was made to the CDI charging to mitigate potential gasgeneration. Two equal portions of CDI were added into solid FIPFA beforeand after solvent addition (through a shot loader). The timing betweenthe two solid CDI additions (4.6 kg each) should not exceed 30 minutes.Then two intermediate filter cakes were dissolved with ethanol. Theexcess ethanol was distilled and replaced with toluene to approximately5% v/v ethanol prior to PD-0325901 recrystallization. Lab studiessuggested that the crystallization from toluene and acetonitrile andrecrystallization from ethanol in toluene would not be able to reduceimpurities which is essential for the polymorph transformation. Thepresence of a dimeric impurity (PF-00191189) at a level greater than0.2% has been known to result in the formation of undesired polymorph.

The crude crystallization from the final reaction mixture reduceddimeric impurity PF-00191189 to approximately 1.9/6 and the subsequentrecrystallization further reduced it to approximately 0.4%. As aconsequence, undesired polymorphs were produced. The DSC patternsindicated two different melting points ˜80° C. (low melt Form II) and˜117° C. (Form I). Also during the processing, the solids crystallizedat a much lower temperature than expected (actual ˜10° C., expected ˜40°C.). It is suspected that the unsuccessful recrystallization is due to achange in the solvent composition as a result of incomplete drying ofthe crude. Drying of the crude wet cake prior to ethanol dissolution wasstopped after about 36 hours when the crude product was ˜28 kg (26 kgtheoretical).

Polymorph Transformation

Approximately 7.4 kg of PD-0325901 (mixed polymorphs) from the finalEtOH/Water crystallization and precipitated materials from the earlierEtOH/Toluene filtrate were taken forward to the polymorphtransformation. Both crops were separately dried in the filter untilconstant weights and each was dissolved in EtOH. The combined EtOHsolution was analyzed by HPLC and resulted in an estimated amount of16.4 kg PD-0325901. The recrystallization was started after removingEtOH via vacuum distillation and adjusting the solvent composition toabout 5% EtOH in Toluene at 65° C. (i.e., EtOH is added dropwise at 65°C. until complete solids dissolution).

A slow 4-hour cooling ramp to 5° C. followed by 12 h stirring wasperformed to ensure satisfactory results. The resulting slurry wasfiltered and again it was completely dried in the filter until constantweight (approximately 3 days). The purified solid showed 99.8% purePD-0325901 with not detected level of dimeric impurity PF-00191189.

The dried solid (15.4 kg) was re-dissolved in exactly 4 volumes of EtOH(62 L) off of the filter, transferred to the reactor and precipitated bya slow (˜3 h) water addition (308 L) at 30-35° C., cooled to 20° C. andstirred for 12 h. The DSC analysis of a slurry sample taken at 2 h showsthe solids to be completely Form IV (desired polymorph).

21.4 kg PD-0315209, 9.7 kg CDI (1.05 equiv.), 91 kg solution of 9.7%PD-0337792 in Toluene (1.1 equiv.) were used and resulted in 12.74 kg ofPD-0325901 (assay 99.4%, 100% Form IV, Yield ˜48%).

Example 2: Assay/Impurities and Identification of PD-0325901

PD-0325901 is separated from process impurities and degradants byreversed-phase liquid chromatography with UV detection at 275 nm.Identification of PD-0325901 is performed by obtaining either aninfrared or proton NMR spectrum, in addition to the HPLC retention time.For purity evaluation, process impurities and degradants are identifiedby their characteristic relative retention times and quantitated by areanormalization.

Chromatographic Conditions: Agilent Zorbax SB C18, 5 μm, 4.6×250 mm (orequivalent); flow rate is 1.0 mL/min; column temperature is 30° C.;detector wavelength is 275 nm; diluent is 50/50 acetonitrile/water;mobile phase A is 0.1% trifluoroacetic acid (TFA) in water; mobile phaseB is methanol; and the gradient conditions below. The assay isdetermined against a reference standard and reported on an anhydrous,solvent free basis. Quantification of specified and unspecifiedimpurities is reported by area percent. Total impurities is the sum ofall impurities present above the reporting threshold of 0.05%.

Time (minutes) 0 15 40 45 46 % mobile phase B 70 70 100 100 70

Example 3: Improved Process for Preparation of Form IV

As described in Example 1, synthetic methods of producing mirdametinibas Form IV produced Form IV with dimeric impurity PF-00191189, andfurther steps were required to transform the product into essentiallypure Form IV without undesired polymorphs Form I and Form II. Therefore,it was necessary to develop a method of producing essentially pure FormIV without additional processing steps.

Mirdametinib Manufacturing Process

The route is a convergent four step synthesis with six chemical stepsoverall, using the proposed starting materials(S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol (SGA),2,3,4-trifluorobenzoic acid (TFBA), 2-fluoro-4-idodoaniline (FIA), andN-hydroxyphthalimide (NHP). The final step (Step 4) provides essentiallypure Form IV of mirdametinib.

Step 1 (Preparation of PD-0337792 (IPGA)): A clean, dry 100-gallonreactor was charged with toluene (139.3 kg, 8 volumes) and(S)-(+)-2,2-Dimethyl-1,3-dioxolane-4-methanol (SGA; 20.0 kg, 1.0equivalents). Triethylamine (18.8 kg, 1.22 equivalents) was charged tothe reactor. The reactor contents were agitated and cooled to −10±10° C.Trifluoromethanesulfonic anhydride (43.5 kg, 1.02 equivalents) was addedto a clean 50-L round bottom flask under nitrogen then cooled to atemperature of ≤−10° C. The cooled trifluoromethanesulfonic anhydridewas slowly transferred to the 100-gallon reactor while maintaining theinternal temperature at −10±10° C. The reaction mixture was agitated at−10±10° C. for 30 minutes. Reaction monitoring by TLC indicated theconversion to be complete. While maintaining the internal temperature at−10±10° C., anhydrous toluene (99.8 kg, 5.75 volumes) was charged to thereactor followed by N-hydroxyphthalimide (26.4 kg, 1.07 equivalents).The contents were warmed to 20±5° C. then agitated at this temperaturefor at least 5 hours, until the triflate intermediate was not detectableby TLC. The reaction mixture was split into two equal portions. Eachtoluene solution was quenched with USP purified water (66 kg, 6.7volumes). The toluene solution was then washed twice with USP purifiedwater (66 kg, 6.7 volumes).

The toluene solutions were recombined in a 100-gallon reactor. Theorganic solution was treated with 28% ammonium hydroxide solution (41.5kg, 7.8 equivalents). The contents were heated to 35±5° C. then agitatedfor not less than (“NLT”) 12 hours. Upon reaction completion, the lower,aqueous phase was removed. The toluene solution was dried via azeotropicdistillation of toluene. The toluene solution was then concentrated tominimum stir volume. The concentrated solution was filtered to removeby-product solids. The cake was washed with toluene and the filtrateswere combined. Assay of the toluene solution indicated 8.6 kg (36.7%yield) of PD-0337792 (IPGA) was present.

Step 2 (Preparation of PD-0315209): A clean, dry 100-gallon reactor waspurged with nitrogen then charged with lithium amide (LiNH2, 8.8 kg, 3.4equivalents) followed by tetrahydrofuran (THF, 56.8 kg, 3.2 volumes).The mixture was cooled to 10±10° C. then additional THF (15.1 kg, 0.85volumes) was charged to the reactor, followed by a solution of2,3,4-trifluorobenzoic acid (TFBA, 20.0 kg, 1.0 equivalent) in THF (26.4kg, 1.15 volumes). The reaction mixture was heated to NMT (“not morethan”) 50° C. A solution of 2-fluoro-4-iodoaniline (FIA, 27.5 kg, 1.02equivalents) in THF (17.8 kg, 1 volumes) was added portion wise to thereactor, maintaining the batch temperature at NMT 50° C. and stirringfor 1 hour between additions. After completing the additions, thereaction mixture stirred for an additional 3 hours at 50±10° C. Uponreaction completion, the mixture was cooled to NMT 10° C. then quenchedwith USP purified water (120.3 kg, 6 volumes). The reaction mixture wasdistilled to approximately 30 gallons after which methyl t-butyl ether(MTBE, 118.6 kg, 8 volumes) was added. The MTBE solution was thenquenched with 2M hydrochloric acid solution (89.5 kg) to a pH=7. Theaqueous phase was then removed. The MTBE solution was filtered throughcelite then washed twice with 5% brine solution (104.1 kg, 5.2 volumes)followed by 1M hydrochloric acid solution (77.4 kg). The MTBE solutionwas solvent swapped with toluene followed by volume adjustment toapproximately 50 gallons. This mixture was heated to 75±5° C. for 1 hourthen cooled to 20±5° C. and stirred for 1 hour. The product wasfiltered, washed with toluene (68.1 kg, ˜4 volumes), then dried undervacuum at 40° C. to obtain 25.2 kg of PD-0315209 (56.4% yield).

Step 3 (Preparation of crude PD-0325901): A clean, dry 100-gallonreactor was purged with nitrogen then charged with PD-0315209 (18.0 kg,1 equivalent) and THF (113.0 kg, 7 volumes). The mixture was cooled to5±5° C. N,N-diisopropylethylamine (15.1 kg, 2.55 equivalents) wascharged maintaining the temperature NMT 25° C. The mixture was cooled to5±5° C. then stirred for 10 minutes. PD-0337792 solution in toluene(121.7 kg total, 1.3 equivalents) was charged to the reactor at 5±5° C.,followed by 50% T3P in ethyl acetate (42.0 kg, 1.45 equivalents). Thereaction mixture stirred at 10±5° C. for NLT 3 hours. An additionalcharge of N,N-diisopropylethylamine (1.9 kg, 0.3 equivalents) and 50%T3P in ethyl acetate (4.1 kg, 0.15 equivalents) were made to advance thecoupling to completion. The reaction was reverse quenched into a 5%sodium hydroxide solution (50 kg), followed by washing with 5% brine(55.4 kg). The organic solution was concentrated then solvent swappedwith toluene. Acetonitrile (43.0 kg, 2.4 volumes) was added to thereactor followed by 2M hydrochloric acid (117.6 kg, 5.1 equivalents).The mixture stirred at 25±5° C. until reaction completion after 16hours. The bottom aqueous was removed then the reaction mixture waswashed with 5% brine (75.2 kg). The organic phase was concentrated thensolvent swapped with toluene to an appropriate volume. The mixture wasthen heated to 75±5° C. for 30 minutes then slowly cooled to 20° C. Thesolids were filtered then washed with toluene (31.1 kg, 1.7 volumes)

The crude solids were charged back to the 100-gallon reactor, followedby 5% ethanol in toluene (170.0 kg). The mixture was heated to 75±5° C.for 60 minutes to achieve a solution then slowly cooled to 20° C. Thesolids were filtered then washed twice with toluene (31 kg, 1.7volumes). The wet cake was dried under vacuum at 45° C. to obtain 8.2 kgof crude PD-0325901 (37.1% yield).

Step 4 (Preparation of Essentially Pure Form IV Mirdametinib): A clean,dry 100-gallon reactor was purged with nitrogen then charged with USPPurified Water (164.1 kg, 20 volumes) followed by ethanol (200 proof,20.8 kg, 3.25 volumes). The solution was heated to 35±5° C. In aseparate vessel, crude PD-0325901 (8.1 kg, 1 equivalent) was dissolvedin ethanol (200 proof, 40.5 kg, 6.3 volumes). A portion of this solution(14.4 kg) was added to the 100-gallon reactor over 60 minutes.PD-0325901 Form IV seeds as prepared in Example 1 (82.6 g, 1% wt) wasadded to the reactor to facilitate precipitation. The remainder of thecrude PD-0325901/ethanol solution (34.3 kg) was added to the reactorover 90 minutes as the mixture stirred at 35±5° C. The reactor contentscontinued to stir at 35±5° C. for 5.5 hours then were slowly cooled to20° C. The solids were then filtered, washed with USP purified water(16.5 kg, 2 volumes), then dried under vacuum at 45° C. for 16 hours.The dried solids were screened through a 10-mesh sieve to obtain 5.7 kgPD-0325901 Form IV (70.4% yield).

An XRPD pattern for essentially pure Form IV used herein is shown inFIG. 1A. TGA and DSC analysis of essentially pure Form IV used hereinare shown in FIG. 1B.

Example 4: Approximate Kinetic Solubility

Solubility of mirdametinib prepared by Example 3 was assessed in 30solvents. The solubility was visually estimated at room temperature (RT;˜23° C.) by dosing small aliquots of solvent into a fixed amount ofsolid (˜10 mg) until the dissolution point or a maximum volume (1.8 mL)was reached. Samples that contained undissolved solids at RT were heatedto 40° C. for 1 hour and the dissolution was assessed visually. Thesolubility data are shown below in Table 1.

TABLE 1 Solubility Solubility (mg/mL)at (mg/mL) # Solvent (v/v) RT (23°C.) at 40° C.  1 Ethanol/Water (9:1 v/v) >424 n/a  2 MeCN/water (8:2v/v) >412 n/a  3 MeCN/Water (7:3 v/v) >408 n/a  4 Dioxane >408 n/a  5DMF (dimethylformamide) >408 n/a  6 2-Propanol: water (9:1 v/v) >400 n/a 7 Acetone >400 n/a  8 Tetrahydrofuran (THF) >396 n/a  9 Acetic acid(HOAc) >388 n/a 10 Dimethyl sulfoxide (DMSO) >388 n/a 11 Methanol(MeOH) >380 n/a 12 Ethanol/Toluene (9:1)  210-420 n/a 13 Ethanol 208-416 n/a 14 1-Propanol  101-202 n/a 15 2-Propanol (IPA)  98-196 n/a16 2-Methyl-2-Butanol  97-194 n/a 17 Ethyl Acetate (EtOAc)  48-95 n/a 18MIBK (4-methyl-2-pentanone)  48-95 n/a 19 Acetonitrile (MeCN)  19-49 n/a20 Nitromethane  10-20 n/a 21 Dimethylcarbonate (DMC)  10-19 n/a 22Trifluoroethanol (TFE)   7-12 n/a 23 Tert-butanol (t-BuOH)   6-10* n/a24 MTBE (methyl-t-butylether)  <6 >6 25 Dichloromethane (DCM)  <6 >6 26Cyclohexane  <6 <6 27 Chloroform  <6 <6 28 Isopropyl ether (IPE)  <6 <629 Toluene  <6 <6 30 Water  <6 <6 n/a-not applicable *solubilitydetermined at 30° C.

Example 5: Comprehensive Crystal-Form Screening

About 450 crystallization experiments were performed using themirdametinib prepared in Example 3 to identify novel polymorphs andsolvates/hydrates of mirdametinib. The description of crystallizationmethods and solid-state forms of the input materials are described here.

Crystallization Modes

Four main types of crystallization modes were employed in the screeningstudy:

Slurry Equilibration:

-   -   Isothermal at 5, 25, and 50° C. for 48-72 hours    -   Thermocycling between 40-5° C. (in one-hour periods) for 48        hours        Rapid and Controlled Cooling of Clarified Solutions of        Mirdametinib:    -   Controlled cooling from 50° C. to 5° C. at a rate of 0.1° C./min        with one hour hold every 5° C. followed by hold at 5° C. for 5        days, followed by hold at −20° C. (for remaining solutions) for        6 to 9 days    -   Rapid cooling from 50° C. to −20° C. at an uncontrolled rate        followed by hold at −20° C. for 4 to 14 days        Rapid and Slow Evaporation of Clarified Solutions of        Mirdametinib:    -   Slow evaporation over up to 30 days at ambient conditions    -   Rapid evaporation for up to 3 days at reduced pressure at        ambient temperature        Addition of Antisolvent to Saturated and Clarified Mirdametinib        Solutions at Room Temperature:    -   Rapid antisolvent addition and stirring at ambient temperature        for up to 11 days

Crystallization Experimental Mode Mode # Exps. Description Input FormsSlurry Thermo-cycled 48 Slurry of mirdametinib stirred Amorphous whilecycling temperature between 5-40° C. for 48 hours Isothermal at 48Slurry' of excess mirdametinib Amorphous Elevated stirred at 50° C. for48 hours Temperature Isothermal at 48 Slurry of excess mirdametinibAmorphous Ambient stirred at 25° C. for >48 hours Temperature Isothermalat 48 Slurry of excess mirdametinib Amorphous Low stirred at 5° C. for72 hours Temperature Solution Controlled 48 Mirdametinib solution FormIV Cooling Cooling equilibrated at ~50° C., filtered, cooled at 0.1°C./min to 5° C. with 1 hour hold every 5° C. and hold 5 days at 5° C.,followed by −20°C storage for 6-9 days for remaining solutions RapidCooling 48 Mirdametinib solution Form IV equilibrated at -50° C.,filtered, crash cooled to −20° C. and hold 4-14 days at −20° C. SolutionFast 48 Solution of mirdametinib Form IV Evaporation Evaporationequilibrated at ambient is filtered and rapidly evaporated under reducedpressure at ambient temperature Slow 48 Solution of mirdametinib Form IVEvaporation equilibrated at ambient is slowly evaporated over up to 30days at ambient conditions Solution Rapid (but 48 Precipitation of themirdametinib Form IV Antisolvent dropwise) from saturated solutioninduced Addition Addition by the addition of an antisolvent. FocusedProcess Solvent 11 Slurry of Toluene Solvate in Various ExperimentsExperiments to Water/Ethanol Spiked with Evaluate Toluene to EvaluateSolvate Risk Solvate Risk, in Mirdametinib Process. Vacuum-OvenVacuum-Oven Drying of Drying, Important Solvates and HydratesDesolvation/ to Determine Stability. Dehydration byDesolvation/Dehydration by Heating Heating of Important SolvatesExperiments and Hydrates to Investigate Total 443 Potential NewNon-Solvated Forms

Example 6: Amorphous Material Preparation and Experiments

Amorphous mirdametinib was prepared on a 100 mg scale by rapidevaporation under reduced pressure (Genevac® vacuum centrifuge) of 100mg/mL solutions of the mirdametinib in methanol and THF (A-1 and A-2,respectfully).

Solutions of mirdametinib (100 mg/mL) were prepared in methanol and THF,and each solution was divided into three equal parts to be used for 1)open at RT stability evaluation, 2) closed at RT stability evaluation,and 3) closed at −20° C. stability evaluation. Observations after rapidevaporation revealed that the samples from methanol were mostly dry,glassy materials, and the samples from THF were mostly sticky, darkamber gums.

PXRD analyses of all six samples (three from both methanol and THF)following rapid evaporation indicated an amorphous state. Other analyses(e.g. PLM, TGA-IR, DSC) were performed on one sample from each solvent.Following initial analyses, one sample from each solvent was stored atRT in an open vial, at RT in a capped vial, and at −20° C. in a cappedvial.

PXRD and PLM analyses after one day showed no crystallization in A-1a(open at RT), and A-1b (capped at RT) from methanol. A-1c (capped at−20° C.) was not analyzed.

PXRD and PLM analyses after one day showed crystallization to Form IV inA-2a (open at RT) from THF. A-2b (capped at RT) and A-2c (capped at −20°C.) were not analyzed.

Since amorphous mirdametinib (A-1) was successfully prepared at 100 mgscale by rapid evaporation at reduced pressure from a methanol solution,this method was used to prepare vials containing amorphous material foruse as the input material for slurry-ripening experiments in the screen.

Amorphous Mirdametinib Experiments

Experiment Procedure Results A-1 A-1: Combined 299.8 ms of mirdametinibwith 3 mL of Amorphous methanol and stirred for 1 hour yielding asolution. Filtered the (after 1 day at solution through 2 μm PTFE filterto clarify. ambient) Pipetted 900 μL of A-1 above into 3 separate 2 mLvials: A-1a, A-1b, and A-1c. Rapidly evaporated the solvent underreduced pressure in a vacuum centrifuge (GeneVac ®) for 20 hours.Products were mostly glassy with a thin film of dark amber on bottom.PXRD and PLM analyses of all 3 samples indicated they were initiallyamorphous. Analyzed A-1a by PLM, TGA-IR, and DSC. DSC data wasconsistent with an amorphous state. TGA-IR showed 1.3% wt. water andMeOH evolved upon heating to 200° C. PXRD and PLM analyses of A-1a,after one day open at RT indicated an amorphous state. A- 2 A-2:Combined 298.9 mg of mirdametinib with 3 mL of THF Form IV and stirredfor 1 hour yielding a solution. Filtered the solution (after 1 day atthrough 2 μm PTFE filter to clarify. ambient) Pipetted 900 μL of A-2above into 3 separate 2 mL vials: A-2a, A-2b, and A-2c. Rapidlyevaporated the solvent under reduced pressure in a vacuum centrifuge(Gene Vac ®) for 20 hours. Product was a dark amber clear gum with someglassy material on top. PXRD and PLM analyses of all three samplesindicated they were initially amorphous. Analyzed A-2a by PLM andTGA-IR. TGA-IR showed 7.8% wt water and THF evolved upon heating to 200°C.. PXRD and PLM analyses of A-2a after one day open at RT showedcrystallization to the supplied Form IV.Characterization of Amorphous Material (A-1)

PXRD and PLM analyses indicated the material was non-crystalline. DSCanalysis showed no melting endotherm up to 200° C., which is consistentwith an amorphous phase. TGA-IR analysis showed about 1.3% wt. loss ofwater and methanol upon heating from 26-200° C. Amorphous mirdametinibwas physically stable in both open and closed vials for at least 24hours at RT.

Example 7: Results of Crystal-Form Screen

The crystal-form screen consisted of about 450 crystallizationexperiments covering crystalline and amorphous input materials, andvarious crystallization modes, solvents, and temperatures.

Four hydrates (designated Forms VI, XIII, XIX and XX) were observed andappear to be novel forms. Water activity experiments conducted betweennon-solvated Form IV and two stable hydrates (Forms VI and XIX)indicated that Form IV is more stable at water activities (aw) 0.6-0.99than hydrate Forms VI and XIX.

Fifteen solvates (designated Forms V, VII-XII, XV-XVIII, and XXI-XXIV)observed included process-related toluene (Form V), toluene/MIBK (FormVIII), and unstable toluene (Form IX) solvates.

Mirdametinib/process solvent conversion studies involving stirring thetoluene solvate (Form V) in 1.1/0.5 (v/v) water/ethanol at RT withvarying amounts of added toluene indicated that if crude mirdametinibfrom toluene/ethanol was the pure toluene solvate, controlling toluenelevels going into the final crystallization could be critical. However,if the crude API is mostly Form IV with lesser amounts of the toluenesolvate, it may not be as critical to monitor toluene levels in thecrude mirdametinib.

Summary of Slurry-Ripening and Evaporative Screening Results

Amorph Amorph Amorph Amorph Fast Slow # Solvent 5 C. 25 C. TC 50 C.Solvent Evap Evap 1 water C C A R A Ethanol A A 2 water:ethanol (80:20v/v) A A A A ethanol:water (95:5 v/v) A C 3 water:ethanol (90:10 v/v) AA A A ethanol:water (90:10 v/v) A C 4 water:ethanol (95:5 v/v) A A A Aethanol:water (80:20 v/v) A C 5 water:metbanol (95:5 v/v) A A Aethanol:toluene (90:10 v/v) A A 6 water:THF (95:5 v/v) A A A Aethanol:toluene (50:50 v/v) A A 7 water:dimethylformamide (95:5 v/v) A AA A ethanol:TFE (90:10 v/v) A A 8 water:dioxane (95:5) A A A Aethanol:DMF (80:20 v/v) A A 9 water:acetone (95:5 v/v) A A A Aethanol:dimethylcarbonate (70:30 v/v) A A 10 water:2-propanol (99:1 v/v)C C R A A Acetone A A 11 cyclohexane A N A A acetone:water (95:5 v/v) AA 12 chloroform A A A A acetone:water (90:10 v/v) A C 13 isopropyl ether(IPE) D D D A D acetone:water (80:20 v/v) A A 14 toluene X B F Bacetone:dichloromethane (90:10 v/v) X A 15 toluene:ethanol (95:5 v/v) BB B acetone:chloroform (90:10 v/v) X 16 toluene:ethanol (85:15 v/v) B BB acetone:isopropyl ether (90:10 v/v) X A 17 toluene:acetone (80:20 v/v)A B B B acetone:tetrahydrofuran (50:50 v/v) A A 18toluene:4-methyl-2-pentanone (80:20 v/v) E F B B acetone:nitromethane(70:30 v/v) N A 19 toluene:ethyl acetate (80:20 v/v) B B F Bacetone:methyl-t-butyl ether (90:10 v/v) A A 20 toluene:2-propanol(80:20 v/v) F B A acetone:DMF (80:20 v/v) A 2 21dimethylcarbonate:ethanol (95:5 v/v) A A A Acetonitrile A A 22trifluoroethanol (TFE) A A A acetonitrile:water (90:10 v/v) A A 23 MTBE(methyl-t-butyl ether) G A G acetonitrile:water (80:20 v/v) A C 24acetonitrile A A A acetonitrile:water (70:30 v/v) C 25acetonitrile:toluene (50:50 v/v) B B B B acetonitrile:DMSO (80:20 v/v) 226 acetontrile:isopropyl ether (50:50 v/v) A A A acetonitrile:DMF (80:20v/v) A 2 27 acetontrile:dichloromethane (50:50 v/v) A A Methanol A A 28dichloromethane:methanol (80:20 v/v) A methanol:nitromethane (80:20 v/v)A C 29 dichloromethane:tetrahydrofuran (80:20 v/v) A A methanol:methylacetate (50:50 v/v) A C 30 dichloromethane:ethanol (80:20 v/v) J2-propanol A A 31 isopropyl ether:methanol (80:20 v/v) A J2-propanol:toluene (90:10 v/v) A A 32 isopropyl ether:tetrahydrofuran(80:20 v/v) J 2-propanol:cyclohexane (90:10 v/v) A A 33chloroform:2-propanol (60:40 v/v) J 2-propanol:dichloromethane (90:10v/v) A A 34 chloroform:dimethylformamide (90:10 v/v) A J2-propanol:chloroform (90:10 v/v) A A 35 dichloromethane:2-propanol(60:40 v/v) J 2-methyl-2-butanol O O 36 dichloromethane:DMSO (90:10 v/v)A A ethyl acetate:dimethyl formamide (70:30 v/v) A 2 37 heptane A A Aethyl acetate A A 38 heptane:ethyl acetate (50:50 v/v) A A A A methylacetate A A 39 heptane:2-propanol (80:20 v/v) A A A A4-methyl-2-pentanone (MIBK) A Q 40 heptane:tetrahydrofuran (90:10 v/v) AA A A J tetrahydrofuran (THF) A 41 heptane:2-butanone (80:20 v/v) A A AA tetrahydrofuran:water (90:10 v/v) A A 42 cyclohexane:acetone (90:10v/v) A A A A tetrahydrofuran:2-butanol (90:10 v/v) A A 43cyclohexane:2-butanone (90:10 v/v) A A A M tetrahydrofuran:cyclohexane(90:10 v/v) A A 44 trifluoroethanol (TFE):ethanol (95:5 v/v) A J Jdioxane:water (90:10 v/v) A A 45 trifluoroethanol (TFE):ethanol (90:10v/v) A J A dioxane:toluene (90:10 v/v) A A 46 nitromethane A A Adioxane:toluene (80:20 v/v) A A 47 nitromethane:1-propanol (95:5 v/v) AA A dioxane:dichloromethane (90:10 v/v) A A 48 dimethylcarbonate (DMC) AA dioxane:cyclohexane (90:10 v/v) A A A Form IV Non-solvated Form IV BForm V Toluene solvate C Form VI Hydrate D Form VII IPE or IPE/Watersolvate E Form VIII Toluene/MIBK solvate F Form IX Unstable Toluenesolvate G Form X MTBE/Water solvate H Form XI Chloroform/IPA solvate IForm XII IPA solvate (isostructural to Form XI) J Form I Non-solvatedForm I K Form XIII Hydrate L Form XIV Transient Non-solv. form (similarto Form IV) M Form XV Cyclohexane solvate N Form XVI Poorly crystallineNitromethane solvate O Form XVII 2-Methyl-2-Butanol solvate P Form XVIIIChloroform/Water solvate Q Form II Non-solvated Form II R Form XIXHydrate S Form XX Hydrate (unstable) T Form XXI 2-Methyl-2-Butanolsolvate 2 (unstable) U Form XXII IPE or IPE/Water solvate 2 V Form XXIIICyclohexane/EtOAc solvate W Form XIV IPE Solvate (unstable todesolvation) X Amorphous No Solid Notes: 1. Some extra peaks of unknowntransient form observed. Some conversion to Form IV observed at ambientconditions. 2. Sample was a solution after 30 days of evaporation. 3.Sample was a solution after 11 days mixing.Summary of Cooling and Solvent-Antisolvent Screening Results

# Solvent RC CC # Solvent Anti-Solvent SAS 1 water:ethanol (60:40 v/v) CA C 1 ethanol water A 2 water:ethanol (50:50 v/v) A C 2 ethanol toluene3 3 water:ethanol (40:60 v/v) 3 ethanol cyclohexane 3 4 water:methanol(40:60 v/v) R A 4 ethanol chloroform 3 5 water:THF (50:50 v/v) C 5ethanol IPE 3 6 water:dimethylformamide (50:50 v/v) 6 MIBK toluene F 7water:dioxane (50:50) 7 MIBK cyclohexane A 8 water:acetone (50:50 v/v) 8MIBK chloroform 3 9 2-propanol I I 9 MIBK IPE 3 10 cyclohexane 10 MeCNwater A 11 chloroform 11 MeCN toluene 3 12 isopropyl ether (IPE) 12 MeCNcyclohexane 3 13 toluene 13 MeCN chloroform 3 14 toluene:ethanol (70:30v/v) B 14 MeCN DCM 3 15 toluene:ethanol (80:20 v/v) B B 15 MeCN IPE 3 16toluene:ethanol (90:10 v/v) B B 16 EtOAc toluene A 17 toluene:acetone(70:30 v/v) 17 EtOAc cyclohexane V 18 toluene:4-methyl-2-pentanone(50:50 v/v) E 18 EtOAc chloroform A 19 toluene:ethyl acetate (50:50 v/v)19 EtOAc IPE D 20 toluene:2-propanol (50:50 v/v) 20 EtOAc DCM 3 21dimethylcarbonate:ethanol (70:30 v/v) A 22 trifluoroethanol(TFE):ethanol (70:30 v/v) A A 23 MTBE (methyl-t-butyl ether):2-propanol(50:50 v/v) 24 acetonitrile S S 25 acetonitrile:toluene (50:50 v/v) 26acetontrile:isopropyl ether (50:50 v/v) A D W 27acetontrile:dichloromethane (50:50 v/v) S 28 dichloromethane:methanol(80:20 v/v) 29 dichloromethane:tetrahydrofuran (80:20 v/v) 30dichloromethane:ethanol (80:20 v/v) 31 isopropyl ether:methanol (80:20v/v) U 32 isopropyl ether:tetrahydrofuran (80:20 v/v) 33chloroform:2-propanol (60:40 v/v) H H 34 chloroform:dimethylformamide(90:10 v/v) 35 dichloromethane:2-propanol (40:60 v/v) 36dichloromethane:dimethyl sulfoxide (50:50 v/v) 37 methyl acetate 38heptane:ethyl acetate (50:50 v/v) A 39 heptane:2-propanol (50:50 v/v) II 40 heptane:tetrahydrofuran (50:50 v/v) 41 heptane:2-butanone (50:50v/v) A A 42 cyclohexane:acetone (40:60 v/v) 43 cyclohexane:2-butanone(40:60 v/v) 44 MIBK (4-methyl-2-pentanone) 45 Ethyl Acetate (EtOAc) 462-methyl-2-butanol T T 47 nitromethane:1-propanol (40:60 v/v) 48dimethylcarbonate (DMC) A 1 A 1 A Form IV Non-solvated Form IV B Form VToluene solvate C Form VI Hydrate D Form VII IPE or IPE/Water solvate EForm VIII Toluene/MIBK solvate F Form IX Unstable Toluene solvate G FormX MTBE/Water solvate H Form XI Chloroform/IPA solvate I Form XII IPAsolvate (isostructural to Form XI) J Form I Non-solvated Form I K FormXIII Hydrate L Form XIV Transient Non-solv. form (similar to Form IV) MForm XV Cyclohexane solvate N Form XVI Poorly crystalline Nitromethanesolvate O Form XVII 2-Methyl-2-Butanol solvate P Form XVIIIChloroform/Water solvate Q Form II Non-solvated Form II R Form XIXHydrate S Form XX Hydrate (unstable) T Form XXI 2-Methyl-2-Butanolsolvate 2 (unstable) U Form XXII IPE or IPE/Water solvate 2 V Form XXIIICyclohexane/EtOAc solvate W Form XXIV IPE Solvate (unstable todesolvation) X Amorphous No Solid Notes: 1. Some extra peaks of unknowntransient form observed. Some conversion to Form IV observed at ambientconditions. 2. Sample was a solution after 30 days of evaporation. 3.Sample was a solution after 11 days mixing.

Example 8: Description of the Obtained Crystal Forms of Mirdametinib

The following sections describe and summarize the physical properties ofeach of the crystal forms observed for mirdametinib.

Transient Non-Solvated Form XIV

The characterization data for Form XIV, a transient non-solvated formvery similar to Form IV, are presented in FIG. 12A and FIG. 12B. PXRDand PLM analysis indicates that the material is crystalline. DSCanalysis shows a single sharp endotherm with onset at about 111° C.(ΔH=85.6 J/g). TGA-IR analysis shows about 0.15% wt. loss to 150° C.,indicating a non-solvated form. Form XIV was found to convert to Form IVwithin four days at ambient conditions. Form XIV was not scaled up to beused for further studies (e.g. relative stability studies).

Toluene Solvate Form V

The characterization data for Form V, a process-relevant toluenesolvate, are presented in FIG. 3A and FIG. 3B. PXRD and PLM analysisindicates that the material is crystalline. DSC analysis shows twooverlapping endotherms with onsets at about 77° C. (ΔH=44.3 J/g) andabout 95° C. (ΔH=33.2 J/g). TGA-IR analysis shows about 2.7% wt. (0.15eq) loss of toluene upon heating to 100° C. and about 4.7% wt. (0.26 eq)total loss of toluene upon heating to 185° C., indicating a solvatedform. Form V was found to be stable at ambient conditions for ≥10 days.Form V was scaled up to be used for focused studies around themirdametinib crystallization process.

Preparation of Form V

Mirdametinib (308.0 mg) was dissolved in 3.0 mL of methanol and thesolution was filtered through a 0.2 μm PTFE filter. The solution wasrapidly evaporated under reduced pressure (GeneVac®) overnight to yieldamorphous material. Toluene (150 μL) and a stir disc was added to theamorphous product and the mixture was stirred at 25° C. for 35 min.Seeds (˜1 mg) were added, and the sample was stirred at 25° C. for 23hours. The damp solids were dried in a nitrogen flow chamber for 3hours. The batch weight was about 212 mg, and the yield was about 69%wt. of Form V.

Form VII (Toluene/MIBK Solvate)

The characterization data for Form VIII, a toluene/MIBK solvate, arepresented FIG. 6A and FIG. 6B. PXRD and PLM analysis indicates that thematerial is crystalline. DSC analysis shows a broad endotherm with onsetat about 81° C. (ΔH=67.1 J/g) followed by a small broad endotherm withonset at about 110° C. (ΔH=7.1 J/g). TGA-IR analysis shows about 3.3%wt. loss of toluene and MIBK upon heating to 112° C. and about 0.8% wt.additional loss of toluene and MIBK upon heating from 112 to 150° C.,indicating a solvated form. Form VIII was stable at ambient conditionsfor ≥2 days. Form VIII was not scaled up for further studies (e.g.,focused studies around the mirdametinib crystallization process).

Unstable Toluene Solvate Form IX

The characterization data for Form IX, an unstable toluene solvate, arepresented in FIG. 7A and FIG. 7B. PXRD and PLM analysis indicates thatthe material is crystalline. DSC analysis shows a broad endotherm withonset at about 84° C. (ΔH=17.1 J/g), an endotherm at about 107° C.(ΔH=12.4 J/g), and a sharper endotherm with onset at about 114° C.(ΔH=39.6 J/g). TGA-IR analysis shows about 4.6% wt. loss of toluene uponheating to 128° C., indicating a solvated form. Form IX exhibitedsignificant conversion toward Form IV after 20 hours at ambientconditions. Form IX was not scaled up for further studies (e.g. focusedstudies around the mirdametinib crystallization process).

Hydrate Form VI

The characterization data for Form VI, a hydrate, are presented in FIG.4A and FIG. 4B. PXRD and PLM analysis indicates that the material iscrystalline. DSC analysis shows three broad endotherms with onsets atabout 41° C. (ΔH=11.4 J/g), about 70° C. (ΔH=48.1 J/g), and about 109°C. (ΔH=21.3 J/g). TGA-IR analysis shows about 2.4% wt. (0.7 eq) loss ofwater upon heating to 125° C., indicating a hydrated form. Form VI wasfound to be stable for ≥2 weeks in solid-state at ambient conditions.Form VI was scaled up to be used for water activity studies betweennon-solvated Form IV and the stable hydrates.

Preparation of Form VI/Form IV Mixture

Mirdametinib (120.8 mg) was dissolved in 1.0 mL of methanol. Thesolution was filtered through a 0.2 μm PTFE filter and rapidlyevaporated under reduced pressure (GeneVac®) overnight. Water (1.0 mL)and a stir disc were added to the dry solids, followed by seeds (˜0.1mg). The suspension was mixed at 25° C. for 24 hours, and the solidswere isolated by vacuum-filtration. The batch weight was about 58 mg,and the yield was an about 48% wt. of a mixture of Form VI and Form IV.

Hydrate Form IX

The characterization data for Form IX, a hydrate, are presented in FIG.7A and FIG. 7B. PXRD and PLM analysis indicates that the material iscrystalline and contains some Form IV. DSC analysis shows two broadendotherms with onsets at about 55° C. (ΔH=66.8 J/g) and about 109° C.(ΔH=25.5 J/g). TGA-IR analysis shows about 3.1% wt. (0.9 eq) loss ofwater upon heating to 100° C., indicating a hydrated form. Form IX wasobserved only once (as phase-pure) during screening, and it was observedto slowly convert to Form IV in solid-state at ambient conditions. FormIX was not scaled up for further studies (e.g., water activity studies).

Hydrate Form XIX

The characterization data for Form XIX, a hydrate, are presented in FIG.17A and FIG. 17B. PXRD and PLM analysis indicates that the material iscrystalline. DSC analysis shows a broad endotherm with onset at about69° C. (ΔH=28.5 J/g), followed by an exotherm with onset at about 98° C.(ΔH=13.5 J/g), and a sharp endotherm with onset at about 115° C.(ΔH=59.6 J/g). TGA-IR analysis shows about 1.85% wt. (0.5 eq) loss ofwater upon heating to 92° C., indicating a hydrated form. Form XIX wasfound to be stable in a capped vial for ≥2 weeks. Form XIX was scaled upto be used for water activity studies between non-solvated Form IV andthe stable hydrates.

Preparation of Form XIX

Mirdametinib (about 497 mg) was dissolved in 3.0 mL of water:MeOH (40:60v/v) by mixing at 50° C. for 10 min. The solution was filtered hotthrough a 0.2 μm PTFE filter into a second vial at 50° C. The solutionwas rapidly cooled to −20° C., and seeds (1-2 mg) were added anddispersed by swirling. After 30 min., the product was a thick paste, so1.0 mL more solvent was added, and the suspension cooled at −20° C. for30 min. The solids in the cold suspension were isolated byvacuum-filtration, then allowed to air dry for 16 hours. The batchweight was about 278 mg, and the yield was about 56% wt. of Form XIX.

Hydrate Form XX

The characterization data for Form XX, a hydrate, are presented in FIG.18A and FIG. 18B. PXRD and PLM analysis indicates that the material iscrystalline. DSC analysis shows three broad endotherms with onsets atabout 77° C. (ΔH=29.0 J/g), about 92° C. (ΔH=9.8 J/g) and about 110° C.(ΔH=6.8 J/g). TGA-IR analysis shows about 2.6% wt. (0.7 eq) loss ofmostly water with a small amount of acetonitrile upon heating to 126°C., indicating a hydrated form. TGA-IR analysis of a secondless-crystalline sample of Form XX showed only water evolved uponheating. Form XX was found to convert to Form IV within 10 days atambient conditions. Form XX was not scaled up for further studies (e.g.,water activity studies).

Other Non-Process Related Solvates (Forms VII, X-XII, XV-XVIII,XXI-XXIV)

A summary of the non-process related solvates (Forms VII, X-XII,XV-XVIII, and XXI-XXIV) is shown in Table 2. The characterization datafor these solvates are shown in FIGS. 5A-5B, 8A-8B, 9A-9B, 10A-10B,13A-13B, 14A-14B, 15A-15B, 16A-16B, 19A-19B, 20A-20B, 21A-21B, and22A-22B.

TABLE 2 Summary of Non-Process Solvates DSC Endotherm Onsets Form Natureof Solvate (approximate ° C.) TGA-IR Data (Wt Loss) VII IPE or IPE/water 85, 110  5.2% isopropyl ether X MTBE/water  89 (2 merged)  2.9% MTBEand water XI Chloroform/IPA  69, 104  7.6% chloroform and IPA XII IPA 72, 109  8.5% IPA (low sample quantity) XV Cyclohexane 104  3.8% (0.2eq.) cyclohexane XVI Nitromethane (poorly crystalline)  74, 102  2.1%(0.2 eq.) (2 merged), 114 nitromethane XVII 2-Methyl-2-Butanol  89  2.7%(0.15 eq.) 2-methyl- 2-butanol XVIII Likely Chloroform  83  1.6%chloroform and water XXI 2-Methyl-2-Butanol  52 (overlap of two), 9014.1% (0.9 eq.) 2-methyl- (converts to Form IV) 2-butanol XXII IPE orIPE/water  65, 89, 102 13.8% isopropyl ether and water XXIIICyclohexane/EtOAc  81, 101  4.4% cyclohexane and EtOAc XXIV IPE orIPE/water 104 (multiple  1.2% isopropyl ether and overlappingendotherms) water

PXRD, TGA, and DSC data for each form presented herein are shown inFIGS. 2A-2B, 3A-3B, 4A-4B, 5A-5B, 6A-6B, 7A-7B, 8A-8B, 9A-91B, 10A-10B,11A-11B, 12A-12B, 13A-13B, 14A-14B, 15A-151B, 16A-16B, 17A-171B,18A-18B, 19A-191B, 20A-20B, 21A-21B, 22A-22B, and 23A-23B.

Example 9: Water Activity Studies of Hydrates at 23° C.

Water activity studies of the stable hydrated Forms VI and XIX wereconducted to determine their relative thermodynamic stabilities. Thestudies were conducted at 23° C. in various water/ethanol mixtures toprovide water activities (aw) from 0.6-0.99. The water activity rangeincludes the approximate water activity of the current final isolationstep of the mirdametinib manufacturing process. Saturated suspensionswere prepared by stirring an excess of mirdametinib in the test solventsfor 16 hours. The suspensions were filtered and transferred ontomixtures containing equivalent amounts of Form VI and Form XIX.

The suspensions were stirred at the target temperatures, sampled atthree and five days and analyzed by PXRD. The results are summarizedbelow and show that all experiments produced Form IV. The hydrates maybe kinetically favored at higher water activities.

Example 10: Drying of Certain Forms Via Vacuum Oven

Drying studies for certain forms were conducted overnight in a vacuumoven at 45° C. After drying, samples were equilibrated to RT for 10 min.and analyzed by PXRD at about 70% ambient lab humidity. The results aresummarized below.

-   -   Form V (Toluene Solvate): Remained unchanged.    -   Form VI (Hydrate): Partially converted to Form A.    -   Form XIII (Hydrate): Form XIII/Form IV mixture converted to Form        IV.    -   Form XIX (Hydrate): Remained unchanged.

Desolvation/dehydration studies of certain forms were conducted in a TGApan with loose lid at a heating rate of 15° C./min from 25 to 100° C.with a 5 min. hold at 100° C. Samples were air-cooled to RT on the TGAand analyzed by PXRD if crystalline. The results are summarized below.

-   -   Form V (Toluene Solvate): After cooling, observed sample to be        molten and transparent dark amber in appearance (melted and        solidified in molten, amorphous state, possible decomposition).    -   Form VI (Hydrate): After cooling, observed sample to be molten        and transparent dark amber in appearance (melted and solidified        in molten, amorphous state, possible decomposition).    -   Form XIX (Hydrate): After cooling, observed sample to be very        slightly sticky, but solid particles (not melted). PXRD        indicated Form I.

Example 11: Toluene-Spiked Slurry Studies

The process-relevant toluene solvate (Form V) was stirred inwater:ethanol (1.1/0.5 v/v) overnight at RT with varying amounts ofadded toluene. The suspensions were filtered, and solids analyzed byPXRD. The results are summarized below.

-   -   With no added toluene, Form V converted to phase-pure Form IV.    -   With 0.5% added toluene (relative to mirdametinib weight), Form        V converted to mostly Form IV with some lesser amount of Form V.    -   With 1% and 2% added toluene, higher relative amounts of Form V        were observed, but difficult to distinguish between 1% and 2%        toluene, since PXRD data was qualitative and variable.

The results of the toluene-spiked slurry studies suggest that if crudemirdametinib from toluene/ethanol was the pure toluene solvate,controlling toluene levels going into the final crystallization would becritical. However, if the crude mirdametinib is mostly Form IV withlesser amounts of the toluene solvate, it may not be as critical tomonitor toluene levels in the crude mirdametinib.

Example 12: Single Crystal X-Ray Diffraction Analysis of Form IV

A suitable single Form IV crystal was analyzed using a Bruker D8 VenturePhoton II CPAD diffractometer equipped with a CuKα INCOATEC Imusmicro-focus source (λ=1.54178 Å). The simulated PXRD pattern wascalculated from the low temperature (100 K) structure and roomtemperature (298 K, 25° C.) unit cell parameters shown below. Unit cellat room temperature was initially determined by Difference Vectorsmethod based on 235 reflections harvested from 151, 1° diffractionframes. Unit cell parameters were subsequently refined during dataintegration by Saint (Bruker (2020). SAINT. Data Reduction Software) andare based on 903 reflections recorded between 19.1 and 1.1 Å resolution.The simulated pattern was consistent with an experimental Form IVpattern as shown in FIG. 1A.

TABLE 3 Initially Determined Unit Cell Parameters at Room Temperaturea[Å] b[Å] c[Å] α[°] β[°] γ[°] V[Å3] 27.080(2) 27.080(2) 4.6971(5) 90 9090 3444.5(8)

TABLE 4 Form IV Crystal Data and Structure Refinement Crystal systemTetragonal Space group P4₁ a/Å  26.9861(4) b/Å  26.9861(4) c/Å  4.66600(10) α/°  90 β/°  90 γ/°  90 Volume/Å³ 3398.01(12) Z   8ρcalcg/cm³   1.885 μ/mm⁻³  15.351 F(000) 1888

Example 13: Capsule Formulations

Formulation Composition 1 mg 2 mg 5 mg % % % Ingredient (w/w) mg/cap(w/w) mg/cap (w/w) mg/cap Mirdametinib^(a) 0.77 1 0.77 2 5.26 5Microcrystalline 93.23 121.2 93.23 242.4 89.74 85.25 Cellulose^(b)Croscarmellose 5 6.5 5 13 5 4.75 sodium Magnesium 1 1.3 1 2.6 0 0Stearate Total 100 130 100 260 100 95 Capsule Shells Size #3 Size #1Size #2 HG HG HG capsules capsules capsules HG—Hard Gelatin ^(a)Based ona theoretical potency of 1.000. Actual quantity may be adjusted based onthe actual potency. ^(b)Quantity of microcrystalline cellulose may beadjusted for slight potency changes of PD-0325901.

Example 14: Dispersible Tablets

Formulation Composition 0.5 mg 1.0 mg Ingredient % (w/w) mg/tab % (w/w)mg/tab Mirdametinib ^(a)  0.75  0.50  0.75  1.00 ^(c) Microcrystalline 90.52 60.60  90.52 121.20^(c) Cellulose ^(b) Croscarmellose  4.85  3.25 4.85  6.50 ^(c) sodium Grape flavor  1.94  1.30  1.94  2.60 Sucralose 0.97  0.65  0.97  1.30 Magnesium Stearate  0.97  0.65  0.97  1.30 ^(c)Total 100.0 66.95 100.0 133.90 a = Based on theoretical potency of1,000. Quantity may be adjusted based on the actual potency. b =Quantity of microcrystalline cellulose may be adjusted for slightpotency changes of mirdametinib c = Excipients are present at the samemg/unit as the 1 mg capsule

All publications, patents, and patent applications mentioned in thisspecification are incorporated herein by reference in their entirety tothe same extent as if each individual publication, patent, or patentapplication was specifically and individually indicated to beincorporated by reference in its entirety. Where a term in the presentapplication is found to be defined differently in a documentincorporated herein by reference, the definition provided herein is toserve as the definition for the term.

While the invention has been described in connection with specificaspects thereof, it will be understood that invention is capable offurther modifications and this application is intended to cover anyvariations, uses, or adaptations following, in general, the principlesand including such departures from the present disclosure that comewithin known or customary practice within the art to which the inventionpertains and can be applied to the essential features hereinbefore setforth, and follows in the scope of the claimed.

In addition to the various embodiments described herein, the presentdisclosure includes the following embodiments numbered E1 through E275.This list of embodiments is presented as an exemplary list and theapplication is not limited to these embodiments.

E1. A crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideof Formula (I)

selected from the group consisting of:

-   a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 5.4±0.2, 17.5±0.2,    and 22.8±0.2 degrees two theta;-   a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 5.9±0.2, 7.2±0.2,    and 21.2±0.2 degrees two theta;-   a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 5.3±0.2, 10.6±0.2,    and 16.1±0.2 degrees two theta;-   a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 5.4±0.2, 10.7±0.2,    and 18.7±0.2 degrees two theta;-   a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 6.7±0.2, 13.5±0.2,    and 22.2±0.2 degrees two theta;-   a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 10.6±0.2, 19.6±0.2,    and 24.8±0.2 degrees two theta;-   a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 5.5±0.2, 6.9±0.2,    and 10.1±0.2 degrees two theta;-   a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 10.1±0.2, 17.3±0.2,    and 22.6±0.2 degrees two theta;-   a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 4.6±0.2, 5.1±0.2,    and 14.6±0.2 degrees two theta;-   a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 4.6±0.2, 23.4±0.2,    and 25.2±0.2 degrees two theta;-   a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 5.5±0.2, 14.7±0.2,    and 20.9±0.2 degrees two theta;-   a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 6.0±0.2, 17.1±0.2,    and 20.6±0.2 degrees two theta;-   a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 5.9±0.2, 10.1±0.2,    and 15.5±0.2 degrees two theta;-   a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 4.6±0.2, 10.7±0.2,    and 15.9±0.2 degrees two theta;-   a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 10.2±0.2, 11.6±0.2,    and 20.0±0.2 degrees two theta;-   a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 7.8±0.2, 14.0±0.2,    and 17.1±0.2 degrees two theta;-   a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 5.5±0.2, 8.2±0.2,    and 16.7±0.2 degrees two theta;-   a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 7.2±0.2, 21.7±0.2,    and 29.1±0.2 degrees two theta;-   a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 5.4±0.2, 9.7±0.2,    and 10.7±0.2 degrees two theta; and-   a crystalline form of    N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide    characterized by an XRPD pattern having peaks at 7.2±0.2, 20.6±0.2,    and 23.0±0.2 degrees two theta.

E2. The crystalline form of E1, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks 5.4±0.2, 17.5±0.2, and22.8±0.2 degrees two theta.

E3. The crystalline form of E2, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks 5.4±0.2, 12.5±0.2,17.5±0.2, and 22.8±0.2 degrees two theta.

E4. The crystalline form of E2 or E3, wherein the TGA exhibits that thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 2.7 wt % between about 35° C. and about 100° C.

E5. The crystalline form of any one of E2-E4, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 77° C.

E6. The crystalline form of any one of E2-E5, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 95° C.

E7. The crystalline form of any one of E2-E6, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 77°C. and a second endotherm onset at about 95° C.

E8. The crystalline form of any one of E2-E7, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 2A.

E9. The crystalline form of any one of E2-E8, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by.

-   -   a) a TGA profile substantially as shown in FIG. 2B; and/or    -   b) a DSC profile substantially as shown in FIG. 2B.

E10. The crystalline form of any one of E2-E9, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form V.

E11. The crystalline form of E1, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.9±0.2, 7.2±0.2,and 21.2±0.2 degrees two theta.

E12. The crystalline form of E11, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.9±0.2, 7.2±0.2,9.3±0.2, and 21.2±0.2 degrees two theta.

E13. The crystalline form of E11 or E12, wherein the TGA exhibits thatthe crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 2.4 wt % between about 25° C. and about 125° C.

E14. The crystalline form of any one of E11-E13, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 41° C.

E15. The crystalline form of any one of E11-E14, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 70° C.

E16. The crystalline form of any one of E11-E15, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 109° C.

E17. The crystalline form of any one of E11-E16, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 41°C., a second endotherm onset at about 70° C., and a third endothermonset at about 109° C.

E18. The crystalline form of E11-E17, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 3A.

E19. The crystalline form of E11-E18, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by:

-   -   a) a TGA profile substantially as shown in FIG. 3B; and/or    -   b) a DSC profile substantially as shown in FIG. 3B.

E20. The crystalline form of any one of E11-E19, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form VI.

E21. The crystalline form of E1, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.3±0.2, 10.6±0.2,and 16.1±0.2 degrees two theta.

E22. The crystalline form of E21, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.3±0.2, 10.6±0.2,13.9±0.2, and 16.1±0.2 degrees two theta.

E23. The crystalline form of E21 or E22, wherein the TGA exhibits thatthe crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 5.2 wt % between about 40° C. and about 120° C.

E24. The crystalline form of any one of E21-E23, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that an endotherm onset at about 85° C.

E25. The crystalline form of any one of E21-E24, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 110° C.

E26. The crystalline form of any one of E21-E25, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 85°C. and a second endotherm onset at about 110° C.

E27. The crystalline form of any one of E21-E26, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 4A.

E28. The crystalline form of any one of E21-E27, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by:

-   -   a) a TGA profile substantially as shown in FIG. 4B; and/or    -   b) a DSC profile substantially as shown in FIG. 4B.

E29. The crystalline form of any one of E21-E28, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form VII.

E30. The crystalline form of E1, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.4±0.2, 10.7±0.2,and 18.7±0.2 degrees two theta.

E31. The crystalline form of E30, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.4±0.2, 10.7±0.2,18.7±0.2, and 23.9±0.2 degrees two theta.

E32. The crystalline form of E30 or E31, wherein the TGA exhibits thatthe crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 3.3 wt % between about 40° C. and about 112° C.

E33. The crystalline form of any one of E30-E32, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 81° C.

E34. The crystalline form of any one of E30-E33, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 110° C.

E35. The crystalline form of any one of E30-E34, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 81°C. and a second endotherm onset at about 110° C.

E36. The crystalline form of any one of E30-E35, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 5A.

E37. The crystalline form of any one of E30-E36, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by:

-   -   a) a TGA profile substantially as shown in FIG. 5B; and/or    -   b) a DSC profile substantially as shown in FIG. 5B.

E38. The crystalline form of any one of E30-E37, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form VIII.

E39. The crystalline form of E1, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 6.7±0.2, 13.5±0.2,and 22.2±0.2 degrees two theta.

E40. The crystalline form of E39, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 6.7±0.2, 8.0±0.2,13.5±0.2, and 22.2±0.2 degrees two theta.

E41. The crystalline form of E39 or E40, wherein the TGA exhibits thatthe crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 4.6 wt % between about 28° C. and about 128° C.

E42. The crystalline form of any one of E39-E41, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 84° C.

E43. The crystalline form of any one of E39-E42, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 107° C.

E44. The crystalline form of any one of E39-E43, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 114° C.

E45. The crystalline form of any one of E39-E44, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 84°C., a second endotherm onset at about 107° C., and a third endothermonset at about 114° C.

E46. The crystalline form of any one of E39-E45, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 6A.

E47. The crystalline form of any one of E39-E46, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by:

-   -   a) a TGA profile substantially as shown in FIG. 6B; and/or    -   b) a DSC profile substantially as shown in FIG. 6B.

E48. The crystalline form of any one of E39-E47, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form IX.

E49. The crystalline of E1, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 10.6±0.2, 19.6±0.2,and 24.8±0.2 degrees two theta.

E50. The crystalline of E49, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.5±0.2, 10.6±0.2,19.6±0.2, and 24.8±0.2 degrees two theta.

E51. The crystalline form of E49 or E50, wherein the TGA exhibits thatthe crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 2.9 wt % between about 40° C. and about 115° C.

E52. The crystalline form of any one of E49-E51, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 89° C.

E53. The crystalline form of any one of E49-E52, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 7A.

E54. The crystalline form of any one of E49-E53, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by.

-   -   a) a TGA profile substantially as shown in FIG. 7B; and/or    -   b) a DSC profile substantially as shown in FIG. 7B.

E55. The crystalline form of any one of E49-E54, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form X.

E56. The crystalline form of E1, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.5±0.2, 6.9±0.2,and 10.1±0.2 degrees two theta.

E57. The crystalline form of E56, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.5±0.2, 6.9±0.2,10.1±0.2, and 19.2±0.2 degrees two theta.

E58. The crystalline form of E56 or E57, wherein the TGA exhibits thatthe crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 7.6 wt % between about 40° C. and about 175° C.

E59. The crystalline form of any one of E56-E58, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 69° C.

E60. The crystalline form of any one of E56-E59, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 104° C.

E61. The crystalline form of any one of E56-E60, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 69°C. and a second endotherm onset at about 104° C.

E62. The crystalline form of any one of E56-E61, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 8A.

E63. The crystalline form of any one of E56-E62, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by:

-   -   a) a TGA profile substantially as shown in FIG. 8B; and/or    -   b) a DSC profile substantially as shown in FIG. 8B.

E64. The crystalline form of any one of E56-E63, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XI.

E65. The crystalline form of E1, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 10.1±0.2, 17.3±0.2,and 22.6±0.2 degrees two theta.

E66. The crystalline form of E65, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 10.1±0.2, 17.3±0.2,21.5±0.2, and 22.6±0.2 degrees two theta.

E67. The crystalline form of E65 or E66, wherein the TGA exhibits thatthe crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 8.5 wt % between about 40° C. and about 160° C.

E68. The crystalline form of any one of E65-E67, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 72° C.

E69. The crystalline form of any one of E65-E68, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 109° C.

E70. The crystalline form of any one of E65-E69, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 72°C. and a second endotherm onset at about 109° C.

E71. The crystalline form of any one of E65-E70, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 9A.

E72. The crystalline form of any one of E65-E71, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by:

-   -   a) a TGA profile substantially as shown in FIG. 9B; and/or    -   b) a DSC profile substantially as shown in FIG. 9B.

E73. The crystalline form of any one of E65-E72, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XII.

E74. The crystalline form of E1, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 4.6±0.2, 5.1±0.2,and 14.6±0.2 degrees two theta.

E75. The crystalline form of E74 wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 4.6±0.2, 5.1±0.2,6.4±0.2, and 14.6±0.2 degrees two theta.

E76. The crystalline form of E74 or E75, wherein the TGA exhibits thatthe crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 3.1 wt % between about 20° C. and about 100° C.

E77. The crystalline form of any one of E74-E76, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 55° C.

E78. The crystalline form of any one of E74-E77, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 109° C.

E79. The crystalline form of any one of E74-E78, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 55°C. and a second endotherm onset at about 109° C.

E80. The crystalline form of any one of E74-E79, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 10A.

E81. The crystalline form of any one of E74-E80, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by:

-   -   a) a TGA profile substantially as shown in FIG. 10B; and/or    -   b) a DSC profile substantially as shown in FIG. 10B.

E82. The crystalline form of any one of E74-E81, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XIII.

E83. The crystalline form of E1, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 4.6±0.2, 23.4±0.2,and 25.2±0.2 degrees two theta.

E84. The crystalline form of E83, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 4.6±0.2, 23.4±0.2,25.2±0.2, and 30.6±0.2 degrees two theta.

E85. The crystalline form of E83 or E84, wherein the TGA exhibits thatthe crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 0.15 wt % between about 40° C. and about 150° C.

E86. The crystalline form of any one of E83-E85, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 111° C.

E87. The crystalline form of any one of E83-E86, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 11A.

E88. The crystalline form of any one of E83-E87, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by.

-   -   a) a TGA profile substantially as shown in FIG. 11B; and/or    -   b) a DSC profile substantially as shown in FIG. 11B.

E89. The crystalline form of any one of E83-E88, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XIV.

E90. The crystalline form of E1, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.5±0.2, 14.7±0.2,and 20.9±0.2 degrees two theta.

E91. The crystalline form of E90, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.5±0.2, 14.7±0.2,20.9±0.2, and 26.6±0.2 degrees two theta.

E92. The crystalline form of E90 or E91, wherein the TGA exhibits thatthe crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 3.8 wt % between about 40° C. and about 150° C.

E93. The crystalline form of any one of E90-E92, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 104° C.

E94. The crystalline form of any one of E90-E93, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 12A.

E95. The crystalline form of any one of E90-E94, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by.

-   -   a) a TGA profile substantially as shown in FIG. 12B; and/or    -   b) a DSC profile substantially as shown in FIG. 12B.

E96. The crystalline form of any one of E90-E95, wherein the crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XV.

E97. The crystalline form of E1, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 6.0±0.2, 17.1±0.2,and 20.6±0.2 degrees two theta.

E98. The crystalline form of E97, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 6.0±0.2, 12.8±0.2,17.1±0.2, and 20.6±0.2 degrees two theta.

E99. The crystalline form of E97 or E98, wherein the TGA exhibits thatthe crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 2.1 wt % between about 40° C. and about 150° C.

E100. The crystalline form of any one of E97-E99, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 74° C.

E101. The crystalline form of any one of E97-E100, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 102° C.

E102. The crystalline form of any one of E97-E101, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 114° C.

E103. The crystalline form of any one of E97-E102, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 74°C., a second endotherm onset at about 102° C., and a third endothermonset at about 114° C.

E104. The crystalline form of any one of E97-E103, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 13A.

E105. The crystalline form of any one of E97-E104, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by.

-   -   a) a TGA profile substantially as shown in FIG. 13B; and/or    -   b) a DSC profile substantially as shown in FIG. 13B.

E106. The crystalline form of any one of E97-E105, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XVI.

E107. The crystalline form of E1, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.9±0.2, 10.1±0.2,and 15.5±0.2 degrees two theta.

E108. The crystalline form of E107, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.9±0.2, 10.1±0.2,11.7±0.2, and 15.5±0.2 degrees two theta.

E109. The crystalline form of E107 or E108, wherein the TGA exhibitsthat the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 2.7 wt % between about 40° C. and about 100° C.

E110. The crystalline form of any one of E107-E109, wherein crystallineform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 89° C.

E111. The crystalline form of any one of E107-E110, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 14A.

E112. The crystalline form of any one of E107-E111, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by.

-   -   a) a TGA profile substantially as shown in FIG. 14B; and/or    -   b) a DSC profile substantially as shown in FIG. 14B.

E113. The crystalline form of any one of E107-E112, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XVII.

E114. The crystalline form of E1, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 4.6±0.2, 10.7±0.2,and 15.9±0.2 degrees two theta.

E115. The crystalline form of E114, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 4.6±0.2, 10.7±0.2,15.9±0.2, and 19.6±0.2 degrees two theta.

E116. The crystalline form of E114 or E115, wherein the TGA exhibitsthat the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 1.6 wt % between about 30° C. and about 150° C.

E117. The crystalline form of any one of E114-E116, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 83° C.

E118. The crystalline form of any one of E114-E117, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 15A.

E119. The crystalline form of any one of E114-E118, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by.

-   -   a) a TGA profile substantially as shown in FIG. 15B; and/or    -   b) a DSC profile substantially as shown in FIG. 15B.

E120. The crystalline form of any one of E114-E119, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XVIII.

E121. The crystalline form of E1, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 10.2±0.2, 11.6±0.2,and 20.0±0.2 degrees two theta.

E122. The crystalline form of E121, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 10.2±0.2, 11.6±0.2,17.1±0.2, and 20.0±0.2 degrees two theta.

E123. The crystalline form of E121 or E122, wherein the TGA exhibitsthat the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 1.85 wt % between about 23° C. and about 92° C.

E124. The crystalline form of any one of E121-E123, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 69° C.

E125. The crystalline form of any one of E121-E124, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 98° C.

E126. The crystalline form of any one of E121-E125, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 115° C.

E127. The crystalline form of any one of E121-E126, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 69°C., a second endotherm onset at about 98° C., and a third endothermonset at about 115° C.

E128. The crystalline form of any one of E121-E127, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 16A.

E129. The crystalline form of any one of E121-E128, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by:

-   -   a) a TGA profile substantially as shown in FIG. 16B; and/or    -   b) a DSC profile substantially as shown in FIG. 16B.

E130. The crystalline form of any one of E121-E129, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XIX.

E131. The crystalline form of E1, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 7.8±0.2, 14.0±0.2,and 17.1±0.2 degrees two theta.

E132. The crystalline form of E131, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 7.8±0.2, 14.0±0.2,15.6±0.2, and 17.1±0.2 degrees two theta.

E133. The crystalline form of E131 or E132, wherein the TGA exhibitsthat the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 2.6 wt % between about 29° C. and about 126° C.

E134. The crystalline form of any one of E131-133, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 77° C.

E135. The crystalline form of any one of E131-E134, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 92° C.

E136. The crystalline form of any one of E131-E135, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 110° C.

E137. The crystalline form of any one of E131-E136, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 77°C., a second endotherm onset at about 92° C., and a third endothermonset at about 110° C.

E138. The crystalline form of any one of E131-E137, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 17A.

E139. The crystalline form of any one of E131-E138, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by:

-   -   a) a TGA profile substantially as shown in FIG. 17B; and/or    -   b) a DSC profile substantially as shown in FIG. 17B.

E140. The crystalline form of any one of E131-E139, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XX.

E141. The crystalline form of E1, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.5±0.2, 8.2±0.2,and 16.7±0.2 degrees two theta.

E142. The crystalline form of E141, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.5±0.2, 8.2±0.2,16.7±0.2, and 17.7±0.2 degrees two theta.

E143. The crystalline form of E141 or E142, wherein the TGA exhibitsthat the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 14.1 wt %4 between about 30° C. and about 110° C.

E144. The crystalline form of any one of E141-E143, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 52° C.

E145. The crystalline form of any one of E141-E144, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 90° C.

E146. The crystalline form of any one of E141-E145, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 52°C. and a second endotherm onset at about 90° C.

E147. The crystalline form of any one of E141-E146, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 18A.

E148. The crystalline form of any one of E141-E147, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by:

-   -   a) a TGA profile substantially as shown in FIG. 18B; and/or    -   b) a DSC profile substantially as shown in FIG. 18B.

E149. The crystalline form of any one of E141-E148, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XXI.

E150. The crystalline form of E1, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 7.2±0.2, 21.7±0.2,and 29.1±0.2 degrees two theta.

E151. The crystalline form of E150, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 7.2±0.2, 18.6±0.2,21.7±0.2, and 29.1±0.2 degrees two theta.

E152. The crystalline form of E150 or E151, wherein the TGA exhibitsthat the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 13.8 wt % between about 26° C. and about 135° C.

E153. The crystalline form of any one of E150-E152, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 65° C.

E154. The crystalline form of any one of E150-E153, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 89° C.

E155. The crystalline form of any one of E150-E154, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 102° C.

E156. The crystalline form of any one of E150-E155, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 65°C., a second endotherm onset at about 89° C., and a third endothermonset at about 102° C.

E157. The crystalline form of any one of E150-E156, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 19A.

E158. The crystalline form of any one of E150-E157, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by:

-   -   a) a TGA profile substantially as shown in FIG. 19B; and/or    -   b) a DSC profile substantially as shown in FIG. 19B.

E159. The crystalline form of any one of E150-E158, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XXII.

E160. The crystalline form of E1, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.4±0.2, 9.7±0.2,and 10.7±0.2 degrees two theta.

E161. The crystalline form of E160, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 5.4±0.2, 6.5±0.2,9.7±0.2, and 10.7±0.2 degrees two theta.

E162. The crystalline form of E160 or E161, wherein the TGA exhibitsthat the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 4.4 wt % between about 27° C. and about 137° C.

E163. The crystalline form of any one of E160-E162, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 81° C.

E164. The crystalline form of any one of E160-E163, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 101° C.

E165. The crystalline form of any one of E160-E164, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has a first endotherm onset at about 81°C. and a second endotherm onset at about 101° C.

E166. The crystalline form of any one of E160-E165, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 20A.

E167. The crystalline form of any one of E160-E166, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by:

-   -   a) a TGA profile substantially as shown in FIG. 20B; and/or    -   b) a DSC profile substantially as shown in FIG. 20B.

E168. The crystalline form of any one of E160-E167, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XXIII.

E169. The crystalline form of E1, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 7.2 0.2, 20.6±0.2,and 23.0±0.2 degrees two theta.

E170. The crystalline form of E169, wherein the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern having peaks at 7.2 0.2, 9.5±0.2,20.6±0.2, and 23.0±0.2 degrees two theta.

E171. The crystalline form of E169 or E170, wherein the TGA exhibitsthat the crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideloses about 1.2 wt % between about 30° C. and about 119° C.

E172. The crystalline form of any one of E169-E171, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideexhibits a DSC thermogram that has an endotherm onset at about 104° C.

E173. The crystalline form of any one of E169-E172, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 21A.

E174. The crystalline form of any one of E169-E173, wherein thecrystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by:

-   -   a) a TGA profile substantially as shown in FIG. 21B; and/or    -   b) a DSC profile substantially as shown in FIG. 21B.

E175. The crystalline form of any one of E169-E174, wherein the crystalform ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis Form XXIV.

E176. Amorphous solid ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideof Formula (I)

E177. The amorphous solid of claim 176, wherein the amorphous solid ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 22A.

E178. The amorphous solid of E176 or E177, wherein the amorphous solidofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by:

-   -   a) a TGA profile substantially as shown in FIG. 22B; and/or    -   b) a DSC profile substantially as shown in FIG. 22B.

E179. A pharmaceutical composition comprising: the crystalline form ofany one of claims 1-175 or the amorphous solid of any one of claims176-178; and one or more pharmaceutically acceptable carriers.

E180. The pharmaceutical composition of E179, wherein the crystallineform or the amorphous solid comprises less than 10% by weight total ofone or more other crystalline forms and/or amorphous solid.

E181. The pharmaceutical composition of E179, wherein the crystallineform or the amorphous solid comprises less than 5% by weight total ofone or more other crystalline forms and/or amorphous solid.

E182. The pharmaceutical composition of E179, wherein the crystallineform or the amorphous solid comprises less than 2% by weight total ofone or more other crystalline forms and/or amorphous solid.

E183. The pharmaceutical composition of E179, wherein the crystallineform or the amorphous solid comprises less than 1% by weight total ofone or more other crystalline forms and/or amorphous solid.

E184. The pharmaceutical composition of E179, wherein the crystallineform or the amorphous solid comprises less than 0.5% by weight total ofone or more other crystalline forms and/or amorphous solid.

E185. The pharmaceutical composition of E179, wherein the crystallineform or the amorphous solid comprises less than 0.1% by weight total ofone or more other crystalline forms and/or amorphous solid.

E186. The pharmaceutical composition of any one of E179-E185, whereinthe pharmaceutical composition is for oral administration.

E187. The pharmaceutical composition of any one of E179-E186, whereinthe pharmaceutical composition is a solid dosage form.

E188. The pharmaceutical composition of any one of E179-E187, whereinthe pharmaceutical composition is a capsule, tablet, powder, granules,minitablet, or pellet.

E189. The pharmaceutical composition of E188, wherein the pharmaceuticalcomposition is a capsule.

E190. The pharmaceutical composition of E189, wherein the capsulecomprises about 1 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the capsule is as follows:

-   -   a) about 0.1 wt/wt % to about 7 wt/wt % of the crystalline form        or the amorphous solid of        N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;    -   b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents;    -   c) about 1 wt/wt % to about 10 wt/wt % of one or more        disintegrants;    -   d) 0 wt/wt % to about 5 wt/wt % of one or more lubricants; and    -   e) a gelatin capsule which encapsulates components a-d.

E191. The pharmaceutical composition of E189, wherein the capsulecomprises about 2 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the capsule is as follows:

-   -   a) about 0.1 wt/wt % to about 7 wt/wt % of the crystalline form        or the amorphous solid of        N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;    -   b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents;    -   c) about 1 wt/wt % to about 10 wt/wt % of one or more        disintegrants;    -   d) 0 wt/wt % to about 5 wt/wt % of one or more lubricants; and    -   e) a gelatin capsule which encapsulates components a-d.

E192. The pharmaceutical composition of E189, wherein the capsulecomprises about 5 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the capsule is as follows:

-   -   a) about 2.5 wt/wt % to about 7.0 wt/wt % of the crystalline        form or the amorphous solid of        N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;    -   b) about 50 wt/wt % to about 98 wt/wt % of one or more diluents;    -   c) about 1 wt/wt % to about 10 wt/wt % of one or more        disintegrants; and    -   d) a gelatin capsule which encapsulates components a-c.

E193. The pharmaceutical composition of any one of E190-E192, wherein atleast one of the diluents is selected from the group consisting ofmicrocrystalline cellulose, lactose, mannitol, sorbitol, xylitol,sucrose, pregelatinized starch, calcium sulfate, calcium carbonate,starch, and dibasic calcium phosphate.

E194. The pharmaceutical composition of E193, wherein at least one ofthe diluents is microcrystalline cellulose.

E195. The pharmaceutical composition of any one of E190-E194, wherein atleast one of the disintegrants is selected from the group consisting ofcroscarmellose sodium, sodium starch glycolate, crospovidone,microcrystalline cellulose, starch, pregelatinized starch, lowsubstituted hydroxypropyl cellulose, and alginic acid.

E196. The pharmaceutical composition of E195, wherein at least one ofthe disintegrants is croscarmellose sodium.

E197. The pharmaceutical composition of any one of E190-E196, wherein atleast one of the lubricants is selected from the group consisting ofmagnesium stearate, sodium stearyl fumarate, glycerol dibehenate,stearic acid, hydrogenated vegetable oil, calcium stearate, zincstearate, beeswax, colloidal silicon dioxide, and talc.

E198. The pharmaceutical composition of E197, wherein at least one ofthe lubricants is magnesium stearate.

E199. The pharmaceutical composition of E188, wherein the pharmaceuticalcomposition is a tablet.

E200. The pharmaceutical composition of E199, wherein the tablet is adispersible tablet.

E201. The pharmaceutical composition of E200, wherein the dispersibletablet comprises about 0.5 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,and wherein each component of the dispersible tablet is as follows:

-   -   a. about 0.1 wt/wt % to about 7 wt/wt % of the crystalline form        or the amorphous solid of        N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;    -   b. about 50 wt/wt % to about 98 wt/wt % of one or more diluents;    -   c. about 1 wt/wt % to about 10 wt/wt % of one or more        disintegrants;    -   d. 0 wt/wt % to about 5 wt/wt % of one or more flavoring agents;    -   e. 0 wt/wt % to about 5 wt/wt % of one or more sweeteners; and    -   f. 0 wt/wt % to about 5 wt/wt % of one or more lubricants.

E202. The pharmaceutical composition of E200, wherein the dispersibletablet comprises about 1 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,and wherein each component of the dispersible tablet is as follows:

-   -   a. about 0.1 wt/wt % to about 7 wt/wt % of the crystalline form        or the amorphous solid of        N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;    -   b. about 50 wt/wt % to about 98 wt/wt % of one or more diluents;    -   c. about 1 wt/wt % to about 10 wt/wt % of one or more        disintegrants;    -   d. 0 wt/wt % to about 5 wt/wt % of one or more flavoring agents;    -   e. 0 wt/wt % to about 5 wt/wt % of one or more sweeteners; and    -   f. 0 wt/wt % to about 5 wt/wt % of one or more lubricants.

E203. The pharmaceutical composition of E201 or E202, wherein at leastone of the diluents is selected from the group consisting ofmicrocrystalline cellulose, lactose, mannitol, sorbitol, xylitol,sucrose, pregelatinized starch, calcium sulfate, calcium carbonate,starch, and dibasic calcium phosphate.

E204. The pharmaceutical composition of E203, wherein at least one ofthe diluents is microcrystalline cellulose.

E205. The pharmaceutical composition of any one of E201-E204, wherein atleast one of the disintegrants is selected from the group consisting ofcroscarmellose sodium, sodium starch glycolate, crospovidone,microcrystalline cellulose, starch, pregelatinized starch, lowsubstituted hydroxypropyl cellulose, and alginic acid.

E206. The pharmaceutical composition of E205, wherein at least one ofthe disintegrants is croscarmellose sodium.

E207. The pharmaceutical composition of any one of E201-E206, wherein atleast one of the flavoring agents is selected from the group consistingof natural or synthetic flavors including but not limited to, grapeflavoring, bubble gum flavoring, caramel flavoring, orange flavoring,lemon flavoring, strawberry flavoring, raspberry flavoring, mintflavoring, peppermint flavoring, grapefruit flavoring, pineappleflavoring, pear flavoring, peach flavoring, vanilla flavoring, bananaflavoring, or cherry flavoring.

E208. The pharmaceutical composition of E207, wherein at least one ofthe flavoring agents is grape flavoring.

E209. The pharmaceutical composition of any one of E201-E208, wherein atleast one sweetener of the dispersible tablet is selected from the groupconsisting of sucralose, acesulfame, saccharin, sucrose, xylitol,mannitol, sorbitol, glucose, fructose, and aspartame.

E210. The pharmaceutical composition of E209, wherein the sweetener issucralose.

E211. The pharmaceutical composition of any one of E201-E210, wherein atleast one of the lubricants is selected from the group consisting ofmagnesium stearate, sodium stearyl fumarate, glycerol dibehenate,stearic acid, hydrogenated vegetable oil, calcium stearate, zincstearate, beeswax, colloidal silicon dioxide, and talc.

E212. The pharmaceutical composition of E211, wherein at least one ofthe lubricants is magnesium stearate.

E213. The pharmaceutical composition of any one of E199-E212, whereinthe tablet is an orodispersible tablet.

E214. The pharmaceutical composition of E188, wherein the pharmaceuticalcomposition is a powder.

E215. The pharmaceutical composition of E214, wherein the powder is adispersible powder.

E216. The pharmaceutical composition of E215, wherein the dispersiblepowder comprises about 0.5 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,and wherein each component of the dispersible powder is as follows:

-   -   a. about 0.1 wt/wt % to about 7 wt/wt % of the crystalline form        or the amorphous solid of        N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;    -   b. about 50 wt/wt % to about 98 wt/wt % of one or more diluents;    -   c. about 1 wt/wt % to about 10 wt/wt % of one or more        disintegrants;    -   d. 0 wt/wt % to about 5 wt/wt % of one or more flavoring agents;    -   e. 0 wt/wt % to about 5 wt/wt % of one or more sweeteners; and    -   f. 0 wt/wt % to about 5 wt/wt % of one or more lubricants.

E217. The pharmaceutical composition of E215, wherein the dispersiblepowder comprises about 1 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,and wherein each component of the dispersible powder is as follows:

-   -   a. about 0.1 wt/wt % to about 7 wt/wt % of the crystalline form        or the amorphous solid of        N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;    -   b. about 50 wt/wt % to about 98 wt/wt % of one or more diluents;    -   c. about 1 wt/wt % to about 10 wt/wt % of one or more        disintegrants;    -   d. 0 wt/wt % to about 5 wt/wt % of one or more flavoring agents;    -   e. 0 wt/wt % to about 5 wt/wt % of one or more sweeteners; and    -   f. 0 wt/wt % to about 5 wt/wt % of one or more lubricants.

E218. The pharmaceutical composition of E216 or E217, wherein at leastone of the diluents is selected from the group consisting ofmicrocrystalline cellulose, lactose, mannitol, sorbitol, xylitol,sucrose, pregelatinized starch, calcium sulfate, calcium carbonate,starch, and dibasic calcium phosphate.

E219. The pharmaceutical composition of E218, wherein at least one ofthe diluents is microcrystalline cellulose.

E220. The pharmaceutical composition of any one of E216-E219, wherein atleast one of the disintegrants is selected from the group consisting ofcroscarmellose sodium, sodium starch glycolate, crospovidone,microcrystalline cellulose, starch, pregelatinized starch, lowsubstituted hydroxypropyl cellulose, and alginic acid.

E221. The pharmaceutical composition of E220, wherein at least one ofthe disintegrants is croscarmellose sodium.

E222. The pharmaceutical composition of any one of E216-E221, wherein atleast one of the flavoring agents is selected from the group consistingof natural or synthetic flavors including but not limited to, grapeflavoring, bubble gum flavoring, caramel flavoring, orange flavoring,lemon flavoring, strawberry flavoring, raspberry flavoring, mintflavoring, peppermint flavoring, grapefruit flavoring, pineappleflavoring, pear flavoring, peach flavoring, vanilla flavoring, bananaflavoring, or cherry flavoring.

E223. The pharmaceutical composition of E222, wherein at least one ofthe flavoring agents is grape flavoring.

E224. The pharmaceutical composition of any one of E216-E223, wherein atleast one sweetener of the dispersible powder is selected from the groupconsisting of sucralose, acesulfame, saccharin, sucrose, xylitol,mannitol, sorbitol, glucose, fructose, and aspartame.

E225. The pharmaceutical composition of E224, wherein the sweetener issucralose.

E226. The pharmaceutical composition of any one of E216-E225, wherein atleast one of the lubricants is selected from the group consisting ofmagnesium stearate, sodium stearyl fumarate, glycerol dibehenate,stearic acid, hydrogenated vegetable oil, calcium stearate, zincstearate, beeswax, colloidal silicon dioxide, and talc.

E227. The pharmaceutical composition of E226, wherein at least one ofthe lubricants is magnesium stearate.

E228. The pharmaceutical composition of any one of E215-E227, whereinthe powder is an orodispersible powder.

E229. The pharmaceutical composition of E188, wherein the pharmaceuticalcomposition is granules.

E230. The pharmaceutical composition of E229, wherein the granules aredispersible granules.

E231. The pharmaceutical composition of E230, wherein the dispersiblegranules comprise about 0.5 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,and wherein each component of the dispersible granules is as follows:

-   -   a. about 0.1 wt/wt % to about 7 wt/wt % of the crystalline form        or the amorphous solid of        N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;    -   b. about 50 wt/wt % to about 98 wt/wt % of one or more diluents;    -   c. about 1 wt/wt % to about 10 wt/wt % of one or more        disintegrants;    -   d. 0 wt/wt % to about 5 wt/wt % of one or more flavoring agents;    -   e. 0 wt/wt % to about 5 wt/wt % of one or more sweeteners; and    -   f. 0 wt/wt % to about 5 wt/wt % of one or more lubricants.

E232. The pharmaceutical composition of E230, wherein the dispersiblegranules comprise about 1 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,and wherein each component of the dispersible granules is as follows:

-   -   a. about 0.1 wt/wt % to about 7 wt/wt % of the crystalline form        or the amorphous solid of        N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;    -   b. about 50 wt/wt % to about 98 wt/wt % of one or more diluents;    -   c. about 1 wt/wt % to about 10 wt/wt % of one or more        disintegrants;    -   d. 0 wt/wt % to about 5 wt/wt % of one or more flavoring agents;    -   e. 0 wt/wt % to about 5 wt/wt % of one or more sweeteners; and    -   f. 0 wt/wt % to about 5 wt/wt % of one or more lubricants.

E233. The pharmaceutical composition of E231 or E232, wherein at leastone of the diluents is selected from the group consisting ofmicrocrystalline cellulose, lactose, mannitol, sorbitol, xylitol,sucrose, pregelatinized starch, calcium sulfate, calcium carbonate,starch, and dibasic calcium phosphate.

E234. The pharmaceutical composition of E233, wherein at least one ofthe diluents is microcrystalline cellulose.

E235. The pharmaceutical composition of any one of E231-E234, wherein atleast one of the disintegrants is selected from the group consisting ofcroscarmellose sodium, sodium starch glycolate, crospovidone,microcrystalline cellulose, starch, pregelatinized starch, lowsubstituted hydroxypropyl cellulose, and alginic acid.

E236. The pharmaceutical composition of E235, wherein at least one ofthe disintegrants is croscarmellose sodium.

E237. The pharmaceutical composition of any one of E231-E236, wherein atleast one of the flavoring agents is selected from the group consistingof natural or synthetic flavors including but not limited to, grapeflavoring, bubble gum flavoring, caramel flavoring, orange flavoring,lemon flavoring, strawberry flavoring, raspberry flavoring, mintflavoring, peppermint flavoring, grapefruit flavoring, pineappleflavoring, pear flavoring, peach flavoring, vanilla flavoring, bananaflavoring, or cherry flavoring.

E238. The pharmaceutical composition of E237, wherein at least one ofthe flavoring agents is grape flavoring.

E239. The pharmaceutical composition of any one of E231-E238, wherein atleast one sweetener of the dispersible granules is selected from thegroup consisting of sucralose, acesulfame, saccharin, sucrose, xylitol,mannitol, sorbitol, glucose, fructose, and aspartame.

E240. The pharmaceutical composition of E239, wherein the sweetener issucralose.

E241. The pharmaceutical composition of any one of E231-E240, wherein atleast one of the lubricants is selected from the group consisting ofmagnesium stearate, sodium stearyl fumarate, glycerol dibehenate,stearic acid, hydrogenated vegetable oil, calcium stearate, zincstearate, beeswax, colloidal silicon dioxide, and talc.

E242. The pharmaceutical composition of E241, wherein at least one ofthe lubricants is magnesium stearate.

E243. The pharmaceutical composition of any one of E229-E242, whereinthe granules are orodispersible granules.

E244. The pharmaceutical composition of E188, wherein the pharmaceuticalcomposition is a minitablet.

E245. The pharmaceutical composition of E244, wherein the minitabletsare dispersible minitablets.

E246. The pharmaceutical composition of E245, wherein the dispersibleminitablets comprise about 0.5 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,and wherein each component of the dispersible minitablets is as follows:

-   -   a. about 0.1 wt/wt % to about 7 wt/wt % of the crystalline form        or the amorphous solid of        N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;    -   b. about 50 wt/wt % to about 98 wt/wt % of one or more diluents;    -   c. about 1 wt/wt % to about 10 wt/wt % of one or more        disintegrants;    -   d. 0 wt/wt % to about 5 wt/wt % of one or more flavoring agents;    -   e. 0 wt/wt % to about 5 wt/wt % of one or more sweeteners; and    -   f. 0 wt/wt % to about 5 wt/wt % of one or more lubricants.

E247. The pharmaceutical composition of E245, wherein the dispersibleminitablets comprise about 1 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,and wherein each component of the dispersible minitablets is as follows:

-   -   a. about 0.1 wt/wt % to about 7 wt/wt % of the crystalline form        or the amorphous solid of        N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;    -   b. about 50 wt/wt % to about 98 wt/wt % of one or more diluents;    -   c. about 1 wt/wt % to about 10 wt/wt % of one or more        disintegrants;    -   d. 0 wt/wt % to about 5 wt/wt % of one or more flavoring agents;    -   e. 0 wt/wt % to about 5 wt/wt % of one or more sweeteners; and    -   f. 0 wt/wt % to about 5 wt/wt % of one or more lubricants.

E248. The pharmaceutical composition of E246 or E247, wherein at leastone of the diluents is selected from the group consisting ofmicrocrystalline cellulose, lactose, mannitol, sorbitol, xylitol,sucrose, pregelatinized starch, calcium sulfate, calcium carbonate,starch, and dibasic calcium phosphate.

E249. The pharmaceutical composition of E248, wherein at least one ofthe diluents is microcrystalline cellulose.

E250. The pharmaceutical composition of any one of E246-E249, wherein atleast one of the disintegrants is selected from the group consisting ofcroscarmellose sodium, sodium starch glycolate, crospovidone,microcrystalline cellulose, starch, pregelatinized starch, lowsubstituted hydroxypropyl cellulose, and alginic acid.

E251. The pharmaceutical composition of E250, wherein at least one ofthe disintegrants is croscarmellose sodium.

E252. The pharmaceutical composition of any one of E246-E251, wherein atleast one of the flavoring agents is selected from the group consistingof natural or synthetic flavors including but not limited to, grapeflavoring, bubble gum flavoring, caramel flavoring, orange flavoring,lemon flavoring, strawberry flavoring, raspberry flavoring, mintflavoring, peppermint flavoring, grapefruit flavoring, pineappleflavoring, pear flavoring, peach flavoring, vanilla flavoring, bananaflavoring, or cherry flavoring.

E253. The pharmaceutical composition of E252, wherein at least one ofthe flavoring agents is grape flavoring.

E254. The pharmaceutical composition of any one of E246-E253, wherein atleast one sweetener of the dispersible minitablets is selected from thegroup consisting of sucralose, acesulfame, saccharin, sucrose, xylitol,mannitol, sorbitol, glucose, fructose, and aspartame.

E255. The pharmaceutical composition of E254, wherein the sweetener issucralose.

E256. The pharmaceutical composition of any one of E246-E255, wherein atleast one of the lubricants is selected from the group consisting ofmagnesium stearate, sodium stearyl fumarate, glycerol dibehenate,stearic acid, hydrogenated vegetable oil, calcium stearate, zincstearate, beeswax, colloidal silicon dioxide, and talc.

E257. The pharmaceutical composition of E256, wherein at least one ofthe lubricants is magnesium stearate.

E258. The pharmaceutical composition of any one of E244-E257, whereinthe minitablets are orodispersible minitablets.

E259. The pharmaceutical composition of E188, wherein the pharmaceuticalcomposition is a pellet.

E260. The pharmaceutical composition of E259, wherein the pellets aredispersible pellets.

E261. The pharmaceutical composition of E260, wherein the dispersiblepellets comprise about 0.5 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,and wherein each component of the dispersible pellets is as follows:

-   -   a. about 0.1 wt/wt % to about 7 wt/wt % of the crystalline form        or the amorphous solid of        N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;    -   b. about 50 wt/wt % to about 98 wt/wt % of one or more diluents;    -   c. about 1 wt/wt % to about 10 wt/wt % of one or more        disintegrants;    -   d. 0 wt/wt % to about 5 wt/wt % of one or more flavoring agents;    -   e. 0 wt/wt % to about 5 wt/wt % of one or more sweeteners; and    -   f. 0 wt/wt % to about 5 wt/wt % of one or more lubricants.

E262. The pharmaceutical composition of E260, wherein the dispersiblepellets comprise about 1 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,and wherein each component of the dispersible pellets is as follows:

-   -   a. about 0.1 wt/wt % to about 7 wt/wt % of the crystalline form        or the amorphous solid of        N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;    -   b. about 50 wt/wt % to about 98 wt/wt % of one or more diluents;    -   c. about 1 wt/wt % to about 10 wt/wt % of one or more        disintegrants;    -   d. 0 wt/wt % to about 5 wt/wt % of one or more flavoring agents;    -   e. 0 wt/wt % to about 5 wt/wt % of one or more sweeteners; and    -   f. 0 wt/wt % to about 5 wt/wt % of one or more lubricants.

E263. The pharmaceutical composition of E261 or E262, wherein at leastone of the diluents is selected from the group consisting ofmicrocrystalline cellulose, lactose, mannitol, sorbitol, xylitol,sucrose, pregelatinized starch, calcium sulfate, calcium carbonate,starch, and dibasic calcium phosphate.

E264. The pharmaceutical composition of E263, wherein at least one ofthe diluents is microcrystalline cellulose.

E265. The pharmaceutical composition of any one of E261-E264, wherein atleast one of the disintegrants is selected from the group consisting ofcroscarmellose sodium, sodium starch glycolate, crospovidone,microcrystalline cellulose, starch, pregelatinized starch, lowsubstituted hydroxypropyl cellulose, and alginic acid.

E266. The pharmaceutical composition of E265, wherein at least one ofthe disintegrants is croscarmellose sodium.

E267. The pharmaceutical composition of any one of E261-E266, wherein atleast one of the flavoring agents is selected from the group consistingof natural or synthetic flavors including but not limited to, grapeflavoring, bubble gum flavoring, caramel flavoring, orange flavoring,lemon flavoring, strawberry flavoring, raspberry flavoring, mintflavoring, peppermint flavoring, grapefruit flavoring, pineappleflavoring, pear flavoring, peach flavoring, vanilla flavoring, bananaflavoring, or cherry flavoring.

E268. The pharmaceutical composition of E267, wherein at least one ofthe flavoring agents is grape flavoring.

E269. The pharmaceutical composition of any one of E261-E268, wherein atleast one sweetener of the dispersible pellets is selected from thegroup consisting of sucralose, acesulfame, saccharin, sucrose, xylitol,mannitol, sorbitol, glucose, fructose, and aspartame.

E270. The pharmaceutical composition of E269, wherein the sweetener issucralose.

E271. The pharmaceutical composition of any one of E261-E270, wherein atleast one of the lubricants is selected from the group consisting ofmagnesium stearate, sodium stearyl fumarate, glycerol dibehenate,stearic acid, hydrogenated vegetable oil, calcium stearate, zincstearate, beeswax, colloidal silicon dioxide, and talc.

E272. The pharmaceutical composition of E271, wherein at least one ofthe lubricants is magnesium stearate.

E273. The pharmaceutical composition of any one of E259-E272, whereinthe pellets are orodispersible pellets.

E274. A method of treating a tumor, cancer, or Rasopathy disordercomprising administering to a subject in need of such treatment thepharmaceutical composition of any one of E179-E273.

E275. The method of E274, wherein the tumor is a neurofibroma.

E276. The method of E274 or E275, wherein the tumor is a neurofibromaassociated with Neurofibromatosis Type 1.

E277. The method of any one of claims E274-E276, wherein the tumor isselected from the group consisting of cutaneous neurofibroma, plexiformneurofibroma, optic pathway glioma, low grade glioma, high grade glioma,and malignant peripheral nerve sheath tumor.

E278. The method of E277, wherein the tumor is plexiform neurofibroma.

E279. The method of any one of E274-E278, wherein the subject has beendiagnosed with a Rasopathy disorder selected from the group consistingof neurofibromatosis type 1, neurofibromatosis type 2,cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome,Noonan syndrome, and Noonan syndrome with multiple lentigines.

E280. The method of any one of E274-E279, wherein the cancer is selectedfrom the group consisting of skin cancer, malignant peripheral nervesheath cancer, leukemia, lymphoma, histiocytic neoplasm, lung cancer,breast cancer, ovarian cancer, renal cancer, colorectal cancer, thyroidcancer, cholangiocarcinoma, urothelial cancer, uterine neoplasm, gastriccancer, sarcoma, bladder cancer, head and neck cancer, endometrialcancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer,prostate cancer, oral cancer, cervical cancer, pancreatic cancer,melanoma, hepatocellular cancer, biliary tract cancer, and serouscarcinoma of the peritoneum.

E281. The method of E280, wherein the leukemia is selected from thegroup consisting of acute lymphocytic leukemia, acute myelogenousleukemia, chronic lymphocytic leukemia, and chronic myelogenousleukemia.

E282. The method of E280, wherein the lymphoma is selected from thegroup consisting of B-cell lymphoma, T-cell lymphoma, Burkitt'slymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinalB cell lymphoma, small lymphocytic lymphoma, and Waldenstrommacroglobulinemia.

E283. The method of E280, wherein the lung cancer is selected from thegroup consisting of lung adenocarcinoma, squamous non-small cell lungcancer, non-squamous non-small cell lung cancer, and small cell lungcancer.

E284. The method of any one of E274-E283, wherein the subject bears amutation or other aberration in one or more genes for which the mutationor other aberration causes a gain or loss of function characteristic ofcertain cancers, wherein the mutation or other aberration in one or moregenes is a mutation or other aberration in one or more of KRAS, NRAS,HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.

E285. The method of any one of E274-E284, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 20 mg.

E286. The method of any one of E274-E284, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 10 mg.

E287. The method of any one of E274-E284, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 8 mg.

E288. The method of any one of E274-E284, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 6 mg.

E289. The method of any one of E274-E288, wherein the total daily doseof theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily.

E290. The method of E289, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 0.1 mg to about 20 mg.

E291. The method of E290, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 0.5 mg.

E292. The method of E290, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 1 mg.

E293. The method of E290, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 2 mg.

E294. The method of E290, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 4 mg.

E295. The method of E290, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 6 mg.

E296. The method of E290, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 8 mg.

E297. The method of E290, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 20 mg.

E298. The method of any one of E274-E288, wherein the total daily doseof theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily.

E299. The method of E298, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 0.1 mg to about 10 mgeach.

E300. The method of E298, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 0.5 mg each.

E301. The method of E298, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 1 mg each.

E302. The method of E298, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 2 mg each.

E303. The method of E298, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 3 mg each.

E304. The method of E298, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 4 mg each.

E305. The method of E298, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 10 mg each.

E306. The method of any one of E274-E305, wherein an individual dose oftheN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered as more than one capsule, more than one tablet, morethan one dose of dispersible powder, more than one dose of granules,more than one dose of minitablets, more than one dose of pellets, or acombination thereof.

E307. The method of any one of E274-E306, wherein the pharmaceuticalcomposition is a dispersible tablet, a dispersible powder, dispersiblegranules, dispersible minitablets, or dispersible pellets, and whereinthe dispersible tablet, dispersible powder, dispersible granules,dispersible minitablets, or dispersible pellets is dispersed in apotable liquid prior to administration to the subject.

E308. The method of E307, wherein the subject experiences dysphagiacaused by one or more of: disease of the nervous system, muscleweakening, developmental disability, stroke, injury, anatomical defect,cancer, treatment for cancer, allergic reaction, dementia, memory loss,or cognitive decline.

E309. The method of E307 or E308, wherein the subject is a pediatricsubject.

E310. The method of any one of E274-E309, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) 21 days inwhich the total daily dose is administered; and (b) 7 days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered.

E311. The method of any one of E274-E309, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) 21 consecutivedays in which the total daily dose is administered; followed by (b) 7consecutive days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered.

E312. The method of any one of E274-E309, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) three 7-dayperiods each comprising (i) 5 days in which the total daily dose isadministered and (ii) 2 days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;and (b) 7 days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered.

E313. The method of any one of E274-E309, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) three 7-dayperiods each comprising (i) 5 consecutive days in which the total dailydose is administered and (ii) 2 consecutive days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;followed by (b) 7 consecutive days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered.

E314. The method of any one of E310-E313, wherein the 28-day dosingcycle is repeated up to a total of 24 consecutive 28-day dosing cycles.

E315. Use of the pharmaceutical composition of any one of E179-E273 forthe manufacture of a medicament for treating a tumor, cancer, orRasopathy disorder.

E316. The use of E315, wherein the tumor is a neurofibroma.

E317. The use of E315 or E316, wherein the tumor is a neurofibromaassociated with Neurofibromatosis Type 1.

E318. The use of any one of E315-E317, wherein the tumor is selectedfrom the group consisting of cutaneous neurofibroma, plexiformneurofibroma, optic pathway glioma, low grade glioma, high grade glioma,and malignant peripheral nerve sheath tumor.

E319. The use of E318, wherein the tumor is plexiform neurofibroma.

E320. The use of any one of E315-E319, wherein the subject has beendiagnosed with a Rasopathy disorder selected from the group consistingof neurofibromatosis type 1, neurofibromatosis type 2,cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome,Noonan syndrome, and Noonan syndrome with multiple lentigines.

E321. The use of any one of E315-E320, wherein the cancer is selectedfrom the group consisting of skin cancer, malignant peripheral nervesheath cancer, leukemia, lymphoma, histiocytic neoplasm, lung cancer,breast cancer, ovarian cancer, renal cancer, colorectal cancer, thyroidcancer, cholangiocarcinoma, urothelial cancer, uterine neoplasm, gastriccancer, sarcoma, bladder cancer, head and neck cancer, endometrialcancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer,prostate cancer, oral cancer, cervical cancer, pancreatic cancer,melanoma, hepatocellular cancer, biliary tract cancer, and serouscarcinoma of the peritoneum.

E322. The use of E321, wherein the leukemia is selected from the groupconsisting of acute lymphocytic leukemia, acute myelogenous leukemia,chronic lymphocytic leukemia, and chronic myelogenous leukemia.

E323. The use of E321, wherein the lymphoma is selected from the groupconsisting of B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma,follicular lymphoma, mantle cell lymphoma, primary mediastinal B celllymphoma, small lymphocytic lymphoma, and Waldenstrom macroglobulinemia.

E324. The use of E321, wherein the lung cancer is selected from thegroup consisting of lung adenocarcinoma, squamous non-small cell lungcancer, non-squamous non-small cell lung cancer, and small cell lungcancer.

E325. The use of any one of E315-E324, wherein the subject bears amutation or other aberration in one or more genes for which the mutationor other aberration causes a gain or loss of function characteristic ofcertain cancers, wherein the mutation or other aberration in one or moregenes is a mutation or other aberration in one or more of KRAS, NRAS,HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.

E326. The use of any one of E315-E325, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 20 mg.

E327. The use of any one of E315-E325, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 10 mg.

E328. The use of any one of E315-E325, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 8 mg.

E329. The use of any one of E315-E325, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 6 mg.

E330. The use of any one of E315-E329, wherein the total daily dose oftheN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily.

E331. The use of E330, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 0.1 mg to about 20 mg.

E332. The use of E331, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 0.5 mg.

E333. The use of E331, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 1 mg.

E334. The use of E331, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 2 mg.

E335. The use of E331, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 4 mg.

E336. The use of E331, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 6 mg.

E337. The use of E331, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 8 mg.

E338. The use of E331, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 20 mg.

E339. The use of any one of E315-E329, wherein the total daily dose oftheN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily.

E340. The use of E339, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 0.1 mg to about 10 mgeach.

E341. The use of E340, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 0.5 mg each.

E342. The use of E340, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 1 mg each.

E343. The use of E340, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 2 mg each.

E344. The use of E340, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 3 mg each.

E345. The use of E340, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 4 mg each.

E346. The use of E340, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 10 mg each.

E347. The use of any one of E315-E346, wherein an individual dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered as more than one capsule, more than one tablet, morethan one dose of dispersible powder, more than one dose of granules,more than one dose of minitablets, more than one dose of pellets, or acombination thereof.

E348. The use of any one of E315-E347, wherein the pharmaceuticalcomposition is a dispersible tablet, a dispersible powder, dispersiblegranules, a dispersible minitablet, or a dispersible pellet, and whereinthe dispersible tablet, dispersible powder, dispersible granules,dispersible minitablets, or dispersible pellets is dispersed in apotable liquid prior to administration to the subject.

E349. The use of E348, wherein the subject experiences dysphagia causedby one or more of: disease of the nervous system, muscle weakening,developmental disability, stroke, injury, anatomical defect, cancer,treatment for cancer, allergic reaction, dementia, memory loss, orcognitive decline.

E350. The use of E348 or E349, wherein the subject is a pediatricsubject.

E351. The use of any one of E315-E350, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) 21 days inwhich the total daily dose is administered; and (b) 7 days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered.

E352. The use of any one of E315-E350, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) 21 consecutivedays in which the total daily dose is administered; followed by (b) 7consecutive days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered.

E353. The use of any one of E315-E350, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) three 7-dayperiods each comprising (i) 5 days in which the total daily dose isadministered and (ii) 2 days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;and (b) 7 days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered.

E354. The use of any one of E315-E350, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) three 7-dayperiods each comprising (i) 5 consecutive days in which the total dailydose is administered and (ii) 2 consecutive days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;followed by (b) 7 consecutive days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered.

E355. The use of any one of E351-E354, wherein the 28-day dosing cycleis repeated up to a total of 24 consecutive 28-day dosing cycles.

E356. A method of producingN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideof Formula (I)

the method comprising reacting PD-0315209 (FIPFA) and PD-0337792 (IPGA)with a coupling reagent 1-propylphosphonic anhydride (T3P) to obtain 901Acetonide as shown in Scheme 1:

E357. The method of E356, wherein the 1-propylphosphonic anhydride is insolution.

E358. The method of E356 or E357, wherein the 1-propylphosphonicanhydride is provided as a solution in ethyl acetate.

E359. The method of E356, wherein the method of producingN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideof Formula (I), comprises a) reacting PD-0315209 (FIPFA) and PD-0337792(IPGA) with a coupling reagent that is 1-propylphosphonic anhydride(T3P) to obtain 901 Acetonide; and b) treating 901 Acetonide with acidto formN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideas shown in Scheme II:

E360. The method of E356, wherein the method of producingN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideof Formula (I)

comprises:

-   -   reacting PD-0315209 (FIPFA) and PD-0337792 (IPGA) with a        coupling reagent to obtain 901 Acetonide, and    -   treating 901 Acetonide with acid to form        N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide        according to Scheme III:

E361. A crystalline composition that is essentially pure Form IVN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideprepared by the method of any one of E356-E360.

E362. The crystalline composition of E361, wherein the crystallinecomposition contains ≤0.2% of dimeric impurity PF-00191189.

E363. The crystalline composition of E361 or E362, wherein thecrystalline composition contains about 0.05% to about 0.19% by weight ofdimeric impurity PF-00191189.

E364. The crystalline composition of any one of E361-E363, wherein thecrystalline composition contains no detectable amount of dimericimpurity PF-00191189.

What is claimed is:
 1. A method of treating melanoma in a patient inneed thereof comprising administering to the patient a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and 1 mg to4 mgN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideused to make the pharmaceutical composition is a crystalline form or anamorphous solid ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideof Formula (I)

selected from the group consisting of: a) a crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecharacterized by an XRPD pattern having peaks at 5.4±0.2, 12.5±0.2,17.5±0.2, and 22.8±0.2 degrees two theta; b) a crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecharacterized by an XRPD pattern having peaks at 5.9±0.2, 7.2±0.2,9.3±0.2, and 21.2±0.2 degrees two theta; c) a crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecharacterized by an XRPD pattern having peaks at 5.3±0.2, 10.6±0.2,13.9±0.2, and 16.1±0.2 degrees two theta; d) a crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecharacterized by an XRPD pattern having peaks at 5.4±0.2, 10.7±0.2,18.7±0.2, and 23.9±0.2 degrees two theta; e) a crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecharacterized by an XRPD pattern having peaks at 6.7±0.2, 13.5±0.2, and22.2±0.2 degrees two theta; f) a crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecharacterized by an XRPD pattern having peaks at 5.5±0.2, 10.6±0.2,19.6±0.2, and 24.8±0.2 degrees two theta; g) a crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecharacterized by an XRPD pattern having peaks at 5.5±0.2, 6.9±0.2,10.1±0.2, and 19.2±0.2 degrees two theta; h) a crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecharacterized by an XRPD pattern having peaks at 10.1±0.2, 17.3±0.2,21.5±0.2, and 22.6±0.2 degrees two theta; i) a crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecharacterized by an XRPD pattern having peaks at 4.6±0.2, 5.1±0.2,6.4±0.2, and 14.6±0.2 degrees two theta; j) a crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecharacterized by an XRPD pattern having peaks at 4.6±0.2, 23.4±0.2, and25.2±0.2 degrees two theta; k) a crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecharacterized by an XRPD pattern having peaks at 5.5±0.2, 14.7±0.2,20.9±0.2, and 26.6±0.2 degrees two theta; l) a crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecharacterized by an XRPD pattern having peaks at 6.0±0.2, 12.8±0.2,17.1±0.2, and 20.6±0.2 degrees two theta; m) a crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecharacterized by an XRPD pattern having peaks at 5.9±0.2, 10.1±0.2,11.7±0.2, and 15.5±0.2 degrees two theta; n) a crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecharacterized by an XRPD pattern having peaks at 4.6±0.2, 10.7±0.2,15.9±0.2, and 19.6±0.2 degrees two theta; o) a crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecharacterized by an XRPD pattern having peaks at 10.2±0.2, 11.6±0.2, and20.0±0.2 degrees two theta; p) a crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecharacterized by an XRPD pattern having peaks at 7.8±0.2, 14.0±0.2,15.6±0.2, and 17.1±0.2 degrees two theta; q) a crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecharacterized by an XRPD pattern having peaks at 5.5±0.2, 8.2±0.2,16.7±0.2, and 17.7±0.2 degrees two theta; r) a crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecharacterized by an XRPD pattern having peaks at 7.2±0.2, 21.7±0.2, and29.1±0.2 degrees two theta; s) a crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecharacterized by an XRPD pattern having peaks at 5.4±0.2, 6.5±0.2,9.7±0.2, and 10.7±0.2 degrees two theta; t) a crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecharacterized by an XRPD pattern having peaks at 7.2±0.2, 20.6±0.2, and23.0±0.2 degrees two theta; and an amorphous solid ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.2. The method of claim 1, wherein the pharmaceutical compositioncomprises 1 mgN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.3. The method of claim 1, wherein the pharmaceutical compositioncomprises 2 mgN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.4. The method of claim 1, wherein the pharmaceutical compositioncomprises 3 mgN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.5. The method of claim 1, wherein the pharmaceutical compositioncomprises 4 mgN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.6. A method of treating melanoma in a patient in need thereof comprisingadministering a pharmaceutical composition comprising 1 mg to 4 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideof Formula (I)

wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis contained within: a crystalline form characterized by an XRPD patternsubstantially as shown in any one of FIGS. 2A, 3A, 4A, 5A, 6A, 7A, 8A,9A, 10A, 11A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A, or 21A, or anamorphous solid characterized by an XRPD pattern substantially as shownin FIG. 22A.